Advertisement

STAT proteins – Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver

  • Bin Gao
    Correspondence
    Corresponding author. Address: Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Rm 2S-33, Bethesda, MD 20892, USA. Tel.: +1 301 443 3998; fax: +1 301 480 0257.
    Affiliations
    Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
    Search for articles by this author
  • Hua Wang
    Affiliations
    Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
    Search for articles by this author
  • Fouad Lafdil
    Affiliations
    Laboratory of Liver Pathophysiology, INSERM, U955, Créteil F-94000, France

    Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil F-94000, France
    Search for articles by this author
  • Dechun Feng
    Affiliations
    Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
    Search for articles by this author
Open AccessPublished:April 13, 2012DOI:https://doi.org/10.1016/j.jhep.2012.01.029

      Summary

      Since its discovery in the early 1990s, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway has been found to play key roles in regulating many key cellular processes such as survival, proliferation, and differentiation. There are seven known mammalian STAT family members: STAT1, 2, 3, 4, 5a, 5b, and 6. In the liver, activation of these STAT proteins is critical for anti-viral defense against hepatitis viral infection and for controlling injury, repair, inflammation, and tumorigenesis. The identification of functions for these STAT proteins has increased our understanding of liver disease pathophysiology and treatments, while also suggesting new therapeutic modalities for managing liver disease.

      Abbreviations:

      CCl4 (carbon tetrachloride), Con A (concanavalin A), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), IL (interleukin), JAK (Janus kinase), NK (natural killer), SNP (single nucleotide polymorphism), SOCS (suppressor of cytokine signaling), STAT (signal transducer and activator of transcription)

      Keywords

      Introduction

      Alcohol consumption, non-alcoholic steatohepatitis, and viral hepatitis are the three major causes of chronic liver disease; each has a similar disease progression that is characterized by chronic liver inflammation, injury, cirrhosis, and hepatocellular carcinoma (HCC). Liver disease progression is controlled by a wide variety of cellular mediators, including among others cytokines, growth factors, and hormones. Of the various downstream signaling pathways, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has been shown to play a multitude of critical roles in the pathogenesis of liver diseases.
      The JAK–STAT pathway was identified in the early 1990s as a key signaling cascade mediating cytokine receptor-derived signals in mammals [
      • Darnell Jr., J.E.
      • Kerr I.M.
      • Stark G.R.
      Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
      ,
      • Schindler C.
      Cytokines and JAK–STAT signaling.
      ]. In general, upon binding to their receptors, cytokines induce receptor dimerization and subsequent receptor-associated JAK dimerization. The JAKs then autophosphorylate one another, and receptor phosphorylation follows. Next, the phosphorylated JAK-receptor complex recruits and phosphorylates various STAT proteins. The phosphorylated STATs then form homodimers or heterodimers and translocate into the nucleus to induce the transcription of genes that regulate many cellular functions [
      • Darnell Jr., J.E.
      • Kerr I.M.
      • Stark G.R.
      Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
      ,
      • Schindler C.
      Cytokines and JAK–STAT signaling.
      ]. To date, four JAKs (JAK1–3 and Tyk2) and seven STAT proteins (STAT1–4, 5a, 5b, and 6) have been identified. Each cytokine receptor activates its characteristic set of individual JAKs and STATs that is determined by the structure of receptor intracellular domains. In the liver, the JAK–STAT pathway is activated by growth hormone and a diverse array of cytokines [
      • Gao B.
      Cytokines, STATs and liver disease.
      ], and to a lesser extent by other mediators such as growth factors (e.g. epidermal growth factor) [
      • Ruff-Jamison S.
      • Chen K.
      • Cohen S.
      Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei.
      ] and viral proteins (e.g. HCV core protein) [
      • Machida K.
      • Tsukamoto H.
      • Liu J.C.
      • Han Y.P.
      • Govindarajan S.
      • Lai M.M.
      • et al.
      C-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair.
      ]. Fig. 1, Fig. 2 show the simple models of JAK–STAT pathways activated by interferons (IFNs), interleukin-6 (IL-6), and IL-22. Table 1, Table 2 list the major activators and functions of each STAT in liver parenchymal (hepatocytes) and non-parenchymal cells.
      Figure thumbnail gr1
      Fig. 1Anti-viral effects of STAT1 and STAT2 in viral hepatitis. Virus-infected cells produce both IFN-α/β and IFN-λ, which bind to their corresponding receptors and activate STAT1 and STAT2 in human hepatocytes. Activated STAT1 and STAT2 induce many anti-viral proteins (e.g. Mx1, OAS, IRF-7, etc.) that subsequently inhibit HCV replication. Although IFN-α/β stimulation also induces strong STAT3 activation in hepatocytes
      [
      • Radaeva S.
      • Jaruga B.
      • Hong F.
      • Kim W.H.
      • Fan S.
      • Cai H.
      • et al.
      Interferon-alpha activates multiple STAT signals and down-regulates c- Met in primary human hepatocytes.
      ]
      , the role of STAT3 in the anti-viral activity of IFN-α/β against HCV remains unknown. IFN-α/β usually induces transient STAT1 and STAT2 activation. In contrast, IFN-λ induces prolonged STAT activation, which may be responsible for the protective effects of IFN-λ on spontaneous and treatment-induced HCV clearance. In addition, IFN-α therapy induces STAT1 activation in NK cells and subsequent NK cell activation. The activated NK cells may also contribute to the anti-viral effects of IFN-α therapy against HCV, which is needed to be confirmed by further studies. IFN-α also activates STAT1 in hematopoietic and neuronal cells that express both IFNAR1 and IFNAR2, resulting in the various side effects associated with IFN-α therapy. IFN-λR1 (IL-28R1) is largely restricted to hepatocytes and is not expressed on immune cells. Thus, IFN-λ treatment is less likely to induce the hematopoietic and neurological side effects associated with IFN-α therapy. IRF-9, interferon regulatory factor 9; ISGF3, interferon-stimulated gene factor 3 complex; ISRE, interferon-sensitive response element; ISG, interferon stimulated gene.
      Figure thumbnail gr2
      Fig. 2Hepatocyte STAT1 and STAT3 in liver injury, inflammation, and regeneration. While STAT1 in hepatocytes is predominantly activated by IFN-γ, STAT3 in hepatocytes is predominantly activated by IL-6, IL-6 family cytokines, and IL-22. Following activation, STAT1 dimerizes and translocates into the nucleus to induce the transcription of many genes that promote liver injury and inflammation and inhibit liver regeneration. In contrast, activated STAT3 induces the expression of many genes that mitigate liver injury and promote liver regeneration. Under most conditions, activation of hepatic STAT3 blocks liver inflammation by inhibiting pro-inflammatory STAT1 signaling and protecting against liver injury. However, hepatic STAT3 may also promote liver inflammation by inducing the production of hepatocyte-derived acute phase proteins. STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS1 and SOCS3 proteins, respectively. ISG, Interferon Stimulated Gene; GAS, Interferon-Gamma Activated Sequence.
      Table 1Major activators and functions of STAT proteins in liver parenchymal cells (hepatocytes).
      References are cited in the text.
      Table 2Major activators and functions of STAT proteins in liver non-parenchymal cells (HSCs, Kupffer cells, sinusoidal endothelial cells) and liver lymphocytes.
      References are cited in the text.
      After activation, the JAK–STAT pathway is usually rapidly terminated by three families of proteins, including suppressors of cytokine signaling (SOCSs), SH2-containing phosphatases (SHPs), and protein inhibitors of activated STATs (PIASs) [
      • Wormald S.
      • Hilton D.J.
      Inhibitors of cytokine signal transduction.
      ,
      • Alexander W.S.
      • Hilton D.J.
      The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response.
      ]. Among them, SOCS proteins, which include SOCS1–3, are cytokine-induced negative feedback-loop regulators that terminate JAK–STAT signaling by binding and inhibiting JAKs or by competing with STATs for phosphotyrosine binding sites on cytokine receptors [
      • Wormald S.
      • Hilton D.J.
      Inhibitors of cytokine signal transduction.
      ,
      • Alexander W.S.
      • Hilton D.J.
      The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response.
      ]. In concanavalin A (Con A)-induced T cell hepatitis model, IFN-γ activation of STAT1 is mainly responsible for SOCS1 induction, whereas IL-6 activation of STAT3 contributes to SOCS3 induction [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ]. SOCS1 and SOCS3 reciprocally inhibit STAT1 and STAT3 signaling with SOCS1 preferential inhibition of IFN-γ signaling and SOCS3 preferential inhibition of IL-6 signaling in the liver [
      • Croker B.A.
      • Krebs D.L.
      • Zhang J.G.
      • Wormald S.
      • Willson T.A.
      • Stanley E.G.
      • et al.
      SOCS3 negatively regulates IL-6 signaling in vivo.
      ].
      In this review, we highlight the important functions of various STATs in hepatic anti-viral responses, inflammation, and tumorigenesis.

      Anti-viral effects of STAT1 and STAT2 in viral hepatitis

      It has been well documented that activation of both STAT1 and STAT2 plays a key role not only in host defense against HCV infection but also in IFN-α treatment-induced HCV clearance. After HCV infection, the infected hepatocytes produce IFN-β, which then activates STAT1 and STAT2 in uninfected neighboring hepatocytes via the binding of IFN-α/β receptor, and subsequently upregulates expression of various anti-viral proteins that prevent further infection [
      • Rehermann B.
      Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence.
      ]. The current standard therapy for chronic HCV infection is 24 or 48 weeks of treatment with pegylated IFN-α given in combination with ribavirin; this leads to viral eradication in approximately 50–60% of treated patients. The anti-HCV effects of IFN-α are believed to be mediated by signaling through a heterodimeric receptor complex composed of IFN-α receptor 1 (IFNAR1) and IFNAR2 on hepatocytes; receptor ligation results in the activation of STAT1 and STAT2 and the subsequent induction of a variety of anti-viral proteins that inhibit HCV replication (Fig. 1). Recent studies suggest that IFN-α-mediated natural killer (NK) cell activation and the subsequent elimination of HCV-infected hepatocytes by NK cells may also contribute to the anti-viral effect of IFN-α treatment against HCV infection [
      • Ahlenstiel G.
      • Titerence R.H.
      • Koh C.
      • Edlich B.
      • Feld J.J.
      • Rotman Y.
      • et al.
      Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.
      ,
      • Cheent K.
      • Khakoo S.I.
      Natural killer cells and hepatitis C: action and reaction.
      ,
      • Golden-Mason L.
      • Cox A.L.
      • Randall J.A.
      • Cheng L.
      • Rosen H.R.
      Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.
      ,
      • Amadei B.
      • Urbani S.
      • Cazaly A.
      • Fisicaro P.
      • Zerbini A.
      • Ahmed P.
      • et al.
      Activation of natural killer cells during acute infection with hepatitis C virus.
      ,
      • Stegmann K.A.
      • Bjorkstrom N.K.
      • Veber H.
      • Ciesek S.
      • Riese P.
      • Wiegand J.
      • et al.
      Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.
      ,
      • Ahlenstiel G.
      • Edlich B.
      • Hogdal L.J.
      • Rotman Y.
      • Noureddin M.
      • Feld J.J.
      • et al.
      Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C.
      ]. NK cells can also produce IFN-γ that subsequently inhibits HCV replication in hepatocytes [
      • Wang S.H.
      • Huang C.X.
      • Ye L.
      • Wang X.
      • Song L.
      • Wang Y.J.
      • et al.
      Natural killer cells suppress full cycle HCV infection of human hepatocytes.
      ]. STAT1 protein expression and phosphorylation in NK cells are increased in HCV patients compared with healthy subjects [
      • Miyagi T.
      • Takehara T.
      • Nishio K.
      • Shimizu S.
      • Kohga K.
      • Li W.
      • et al.
      Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection.
      ,
      • Edlich B.
      • Ahlenstiel G.
      • Azpiroz A.Z.
      • Stoltzfus J.
      • Noureddin M.
      • Serti E.
      • et al.
      Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C.
      ], and are further elevated during IFN-α therapy [
      • Edlich B.
      • Ahlenstiel G.
      • Azpiroz A.Z.
      • Stoltzfus J.
      • Noureddin M.
      • Serti E.
      • et al.
      Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C.
      ]. Elevation of STAT1 in NK cells correlates with increased NK cell cytotoxicity and the anti-viral effectiveness of IFN-α-based therapy, suggesting that STAT1 contributes to NK cell activation and the anti-HCV activity of IFN-α [
      • Edlich B.
      • Ahlenstiel G.
      • Azpiroz A.Z.
      • Stoltzfus J.
      • Noureddin M.
      • Serti E.
      • et al.
      Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C.
      ] (Fig. 1).
      IFN-λ proteins are known as type III IFNs that are functionally similar to IFN-α in that they can also activate STAT1 and STAT2. To date, three IFN-λ genes that encode three distinct, yet highly related, proteins known as IFN-λ1 (also known as IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B) have been identified [
      • Donnelly R.P.
      • Kotenko S.V.
      Interferon-lambda: a new addition to an old family.
      ]. In this article, we use IL-29, IL-28A and IL-28B to represent the gene symbols of IFN-λs, as recommended by the Human Genome Organization Gene Nomenclature Committee, and use IFN-λs to represent the corresponding proteins to emphasize their functions. IFN-λ can initiate STAT1 and STAT2 activation by binding to a receptor complex comprised of the IL-10R2 and the unique IFN-λR1 (also known as IL-28R) chain. The subsequent upregulation of a number of anti-viral proteins leads to the inhibition of HCV replication [
      • Diegelmann J.
      • Beigel F.
      • Zitzmann K.
      • Kaul A.
      • Goke B.
      • Auernhammer C.J.
      • et al.
      Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.
      ,
      • Marcello T.
      • Grakoui A.
      • Barba-Spaeth G.
      • Machlin E.S.
      • Kotenko S.V.
      • MacDonald M.R.
      • et al.
      Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
      ,
      • Donnelly R.P.
      • Dickensheets H.
      • O’Brien T.R.
      Interferon-lambda and therapy for chronic hepatitis C virus infection.
      ,
      • Zhang L.
      • Jilg N.
      • Shao R.X.
      • Lin W.
      • Fusco D.N.
      • Zhao H.
      • et al.
      IL28B inhibits hepatitis C virus replication through the JAK–STAT pathway.
      ,
      • Pagliaccetti N.E.
      • Eduardo R.
      • Kleinstein S.H.
      • Mu X.J.
      • Bandi P.
      • Robek M.D.
      Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication.
      ,
      • Robek M.D.
      • Boyd B.S.
      • Chisari F.V.
      Lambda interferon inhibits hepatitis B and C virus replication.
      ] (Fig. 1). As the expression of IFN-λR1 is largely restricted to epithelial cells, clinical treatment with IFN-λ is less likely to induce the hematopoietic and neurologic side effects observed during IFN-α therapy [
      • Donnelly R.P.
      • Dickensheets H.
      • O’Brien T.R.
      Interferon-lambda and therapy for chronic hepatitis C virus infection.
      ]. Based on these exciting preclinical findings, several groups have performed phase I clinical trials with pegylated IFN-λ1. In these trials, HCV-infected patients tolerated weekly pegylated IFN-λ1 treatments with or without daily ribavirin for 4 weeks and had clear anti-viral responses [
      • Muir A.J.
      • Shiffman M.L.
      • Zaman A.
      • Yoffe B.
      • de la Torre A.
      • Flamm S.
      • et al.
      Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.
      ,
      • Ramos E.L.
      Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C.
      ]. However, large, randomized controlled trials are needed to provide clear data regarding the safety and efficacy of pegylated IFN-λ1 for the treatment of chronic HCV infections.
      In addition to the potential of IFN-λ to treat HCV, single nucleotide polymorphisms (SNPs) in the IL-28B/IFN-λ3 gene have been shown to play important roles in regulating spontaneous HCV clearance and in determining the efficacy of pegylated IFN-α plus ribavirin therapy in HCV patients. As the details of these genetic studies have been discussed in several reviews [
      • Afdhal N.H.
      • McHutchison J.G.
      • Zeuzem S.
      • Mangia A.
      • Pawlotsky J.M.
      • Murray J.S.
      • et al.
      Hepatitis C pharmacogenetics: state of the art in 2010.
      ,
      • Balagopal A.
      • Thomas D.L.
      • Thio C.L.
      IL28B and the control of hepatitis C virus infection.
      ,
      • Lange C.M.
      • Zeuzem S.
      IL28B single nucleotide polymorphisms in the treatment of hepatitis C.
      ], we will only briefly summarize the findings here. First, SNPs in the IL-28B gene, such as rs12979860 or rs809917, are strongly associated with spontaneous and IFN-α treatment-induced clearance of HCV in patients infected with either HCV genotypes 1 or 4; however, the results from studies in patients with HCV genotypes 2 and 3 remain inconclusive (see reviews [
      • Afdhal N.H.
      • McHutchison J.G.
      • Zeuzem S.
      • Mangia A.
      • Pawlotsky J.M.
      • Murray J.S.
      • et al.
      Hepatitis C pharmacogenetics: state of the art in 2010.
      ,
      • Balagopal A.
      • Thomas D.L.
      • Thio C.L.
      IL28B and the control of hepatitis C virus infection.
      ,
      • Lange C.M.
      • Zeuzem S.
      IL28B single nucleotide polymorphisms in the treatment of hepatitis C.
      ]). Second, the presence of IL-28B gene SNPs, in either donor or recipient tissues, has been shown to affect the responsiveness to IFN-α therapy for the treatment of recurrent HCV infection following liver transplantation [
      • Lange C.M.
      • Moradpour D.
      • Doehring A.
      • Lehr H.A.
      • Mullhaupt B.
      • Bibert S.
      • et al.
      Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.
      ,
      • Fukuhara T.
      • Taketomi A.
      • Motomura T.
      • Okano S.
      • Ninomiya A.
      • Abe T.
      • et al.
      Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.
      ,
      • Charlton M.R.
      • Thompson A.
      • Veldt B.J.
      • Watt K.
      • Tillmann H.
      • Poterucha J.J.
      • et al.
      Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.
      ]. Although the association between IL-28B SNPs and HCV infection has been extensively investigated, the results for the association of these SNPs and IFN-λ protein expression have been controversial. It was reported that patients with the IL-28B rs12979860 SNP had increased serum levels of IFN-λs that were associated with HCV clearance [
      • Langhans B.
      • Kupfer B.
      • Braunschweiger I.
      • Arndt S.
      • Schulte W.
      • Nischalke H.D.
      • et al.
      Interferon-lambda serum levels in hepatitis C.
      ], but other reports showed that patients with the response-favorable IL-28B rs8099917 TT genotype had a lower expression of IFN-λs compared to patients with the TG or GG genotypes [
      • Abe H.
      • Hayes C.N.
      • Ochi H.
      • Maekawa T.
      • Tsuge M.
      • Miki D.
      • et al.
      IL28 variation affects expression of interferon stimulated genes and peg-interferon and ribavirin therapy.
      ], or that IL-28B SNPs were not associated with intrahepatic IFN-λ expression in HCV patients [
      • Urban T.J.
      • Thompson A.J.
      • Bradrick S.S.
      • Fellay J.
      • Schuppan D.
      • Cronin K.D.
      • et al.
      IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.
      ]. Moreover, the mechanisms underlying the important functions of IL-28B SNPs in controlling HCV outcomes remain obscure. It may be related to IFN-λ-mediated direct inhibition of HCV replication [
      • Marcello T.
      • Grakoui A.
      • Barba-Spaeth G.
      • Machlin E.S.
      • Kotenko S.V.
      • MacDonald M.R.
      • et al.
      Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
      ,
      • Pagliaccetti N.E.
      • Eduardo R.
      • Kleinstein S.H.
      • Mu X.J.
      • Bandi P.
      • Robek M.D.
      Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication.
      ,
      • Robek M.D.
      • Boyd B.S.
      • Chisari F.V.
      Lambda interferon inhibits hepatitis B and C virus replication.
      ] and IFN-λ-mediated induction of prolonged STAT1 activation and ISG expression in hepatocytes [
      • Marcello T.
      • Grakoui A.
      • Barba-Spaeth G.
      • Machlin E.S.
      • Kotenko S.V.
      • MacDonald M.R.
      • et al.
      Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
      ,
      • Makowska Z.
      • Duong F.H.
      • Trincucci G.
      • Tough D.F.
      • Heim M.H.
      Interferon-beta and interferon-lambda signaling is not affected by interferon-induced refractoriness to interferon-alpha in vivo.
      ].
      In contrast to the well-documented anti-viral effects of STAT1 and STAT2, the functions of other STATs in viral infection remain largely unknown. Although activation of other STATs appears to have no direct anti-viral effects, their activation may indirectly modulate the anti-viral activity of IFNs by regulating STAT1 and STAT2 activation, modulating IFN expression, and controlling immune cell activation. For example, in addition to the activation of STAT1 and STAT2, IFN-α also induces strong STAT3 activation in primary human hepatocytes [
      • Radaeva S.
      • Jaruga B.
      • Hong F.
      • Kim W.H.
      • Fan S.
      • Cai H.
      • et al.
      Interferon-alpha activates multiple STAT signals and down-regulates c- Met in primary human hepatocytes.
      ]. Although STAT3 activation does not induce anti-viral proteins, it may negatively regulate the anti-viral activity of IFN-α by inhibiting STAT1 and STAT2 activation through several mechanisms. First, STAT3 can heterodimerize with STAT1, thereby reducing STAT1 and STAT2 heterodimer formation. Second, STAT3 activation upregulates SOCS1 and SOCS3 expression that then inhibit IFN-α signaling. In addition, activated STAT3 is an important survival signal for hepatocytes and likely prevents HCV-infected hepatocyte cell death, thereby diminishing the anti-viral effects of IFN-α. Further studies to clarify the role of STAT3 in anti-viral IFN-α therapy may help identify novel strategies to improve the efficacy of IFN-α treatment in HCV patients.

      Opposing roles of STAT1 and STAT3 in liver injury and repair

      Accumulated research data from the last decade suggest that signaling through the JAK–STAT pathway plays key roles in controlling liver injury, regeneration, fibrosis, and inflammation. Interestingly, STAT1 and STAT3 activation play opposing roles in many aspects of liver pathophysiology, including liver injury and repair, which are discussed here. As the roles of the STATs in liver fibrogenesis have been summarized in a recent article [
      • Mair M.
      • Blaas L.
      • Osterreicher C.H.
      • Casanova E.
      • Eferl R.
      JAK–STAT signaling in hepatic fibrosis.
      ], they are not discussed in this review.

      Liver injury

      Liver injury is characterized by damage to parenchymal cells, such as hepatocytes and biliary cells, and also by the sinusoidal disorganization that follows endothelial cell death. Whereas STAT1 activation in hepatocytes is a pro-apoptotic signal that leads to cell death and increased liver damage, STAT3 activation is a survival signal that protects against hepatocyte death. The opposing roles of hepatic STAT1 and STAT3 in liver injury have been extensively characterized in the Con A-induced T cell hepatitis model, where both signals are highly activated [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Torisu T.
      • Nakaya M.
      • Watanabe S.
      • Hashimoto M.
      • Yoshida H.
      • Chinen T.
      • et al.
      Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis.
      ,
      • Lafdil F.
      • Wang H.
      • Park O.
      • Zhang W.
      • Moritoki Y.
      • Yin S.
      • et al.
      Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
      ,
      • Klein C.
      • Wustefeld T.
      • Assmus U.
      • Roskams T.
      • Rose-John S.
      • Muller M.
      • et al.
      The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury.
      ,
      • Siebler J.
      • Wirtz S.
      • Klein S.
      • Protschka M.
      • Blessing M.
      • Galle P.R.
      • et al.
      A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
      ,
      • Zenewicz L.A.
      • Yancopoulos G.D.
      • Valenzuela D.M.
      • Murphy A.J.
      • Karow M.
      • Flavell R.A.
      Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
      ,
      • Ogata H.
      • Kobayashi T.
      • Chinen T.
      • Takaki H.
      • Sanada T.
      • Minoda Y.
      • et al.
      Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.
      ,
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ]. Blockade of hepatic STAT1 activation via genetic modification of several genes prevented Con A-induced liver injury [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Torisu T.
      • Nakaya M.
      • Watanabe S.
      • Hashimoto M.
      • Yoshida H.
      • Chinen T.
      • et al.
      Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis.
      ,
      • Lafdil F.
      • Wang H.
      • Park O.
      • Zhang W.
      • Moritoki Y.
      • Yin S.
      • et al.
      Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
      ,
      • Siebler J.
      • Wirtz S.
      • Klein S.
      • Protschka M.
      • Blessing M.
      • Galle P.R.
      • et al.
      A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
      ,
      • Siebler J.
      • Wirtz S.
      • Frenzel C.
      • Schuchmann M.
      • Lohse A.W.
      • Galle P.R.
      • et al.
      Cutting edge: a key pathogenic role of IL-27 in T cell-mediated hepatitis.
      ]; whereas inhibition of hepatic STAT3 exaggerated it [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Klein C.
      • Wustefeld T.
      • Assmus U.
      • Roskams T.
      • Rose-John S.
      • Muller M.
      • et al.
      The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury.
      ,
      • Zenewicz L.A.
      • Yancopoulos G.D.
      • Valenzuela D.M.
      • Murphy A.J.
      • Karow M.
      • Flavell R.A.
      Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
      ]. Conversely, enhanced hepatic STAT1 activation accelerated Con A-induced hepatitis [
      • Torisu T.
      • Nakaya M.
      • Watanabe S.
      • Hashimoto M.
      • Yoshida H.
      • Chinen T.
      • et al.
      Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis.
      ], while increased hepatic STAT3 activation diminished it [
      • Ogata H.
      • Kobayashi T.
      • Chinen T.
      • Takaki H.
      • Sanada T.
      • Minoda Y.
      • et al.
      Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.
      ,
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ]. These findings suggest that STAT1 activation in hepatocytes is detrimental in Con A-induced hepatitis, whereas activation of hepatic STAT3 is protective. In addition, the detrimental effect of STAT1 has also been reported in LPS plus D-galactosamine-induced liver injury [
      • Kim W.H.
      • Hong F.
      • Radaeva S.
      • Jaruga B.
      • Fan S.
      • Gao B.
      STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
      ]; whereas the hepatoprotective function of hepatic STAT3 has been observed in many models of liver injury [
      • Horiguchi N.
      • Lafdil F.
      • Miller A.M.
      • Park O.
      • Wang H.
      • Rajesh M.
      • et al.
      Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice.
      ,
      • Mair M.
      • Zollner G.
      • Schneller D.
      • Musteanu M.
      • Fickert P.
      • Gumhold J.
      • et al.
      Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.
      ,
      • Kroy D.C.
      • Beraza N.
      • Tschaharganeh D.F.
      • Sander L.E.
      • Erschfeld S.
      • Giebeler A.
      • et al.
      Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice.
      ,
      • Horiguchi N.
      • Wang L.
      • Mukhopadhyay P.
      • Park O.
      • Jeong W.I.
      • Lafdil F.
      • et al.
      Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
      ,
      • Ki S.H.
      • Park O.
      • Zheng M.
      • Morales-Ibanez O.
      • Kolls J.K.
      • Bataller R.
      • et al.
      Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.
      ,
      • Haga S.
      • Terui K.
      • Zhang H.Q.
      • Enosawa S.
      • Ogawa W.
      • Inoue H.
      • et al.
      Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms.
      ]. For example, conditional deletion of STAT3 in hepatocytes markedly increased mice to Fas ligand-induced hepatocyte apoptosis and liver injury [
      • Haga S.
      • Terui K.
      • Zhang H.Q.
      • Enosawa S.
      • Ogawa W.
      • Inoue H.
      • et al.
      Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms.
      ], which is likely mediated by upregulating the expression of anti-apoptotic and anti-oxidant proteins (see reviews [
      • Taub R.
      Hepatoprotection via the IL-6/Stat3 pathway.
      ,
      • Wang H.
      • Lafdil F.
      • Kong X.
      • Gao B.
      Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target.
      ]). Conversely, the deleterious effects of STAT1 in hepatocytes are likely mediated by the direct induction of apoptosis and the upregulation of chemokines and chemokine receptors [
      • Sun R.
      • Park O.
      • Horiguchi N.
      • Kulkarni S.
      • Jeong W.I.
      • Sun H.Y.
      • et al.
      STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
      ,
      • Jaruga B.
      • Hong F.
      • Kim W.H.
      • Gao B.
      IFN-{gamma}/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1.
      ].
      Interestingly, hepatic STAT1 and STAT3 not only functionally antagonize each other, but they also mutually inhibit each other’s activation. For example, inhibition of hepatic STAT3 mediated through deletion of either IL-6 or STAT3 resulted in enhanced STAT1 activation in Con A-induced hepatitis [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ] and partial hepatectomy models [
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ,
      • Li W.
      • Liang X.
      • Kellendonk C.
      • Poli V.
      • Taub R.
      STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration.
      ]. In contrast, deletion of STAT1 resulted in enhanced STAT3 activation in Con A-induced hepatitis model [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ]. The mutual inhibition of STAT1 and STAT3 is mediated, at least in part, through the induction of SOCS1 and SOCS3, respectively, that inhibit both STAT1 and STAT3 activation in Con A-induced hepatitis models [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ] (Fig. 2).

      Liver regeneration

      The mammalian liver has a great ability to regenerate fully after tissue loss or damage, which stimulates quiescent hepatocytes to enter the cell cycle and go through limited replication under the control of the broad spectrum of cytokines, growth factors, and hormones (see reviews [
      • Michalopoulos G.K.
      Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.
      ,
      • Fausto N.
      • Campbell J.S.
      • Riehle K.J.
      Liver regeneration.
      ]). Among these factors, IL-6 represents the major cytokine that activates STAT3 in hepatocytes and is consequently responsible for hepatocyte proliferation following partial hepatectomy originally reported by Cressman et al. [
      • Cressman D.E.
      • Greenbaum L.E.
      • DeAngelis R.A.
      • Ciliberto G.
      • Furth E.E.
      • Poli V.
      • et al.
      Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.
      ]; however, several follow-up studies using IL-6 knockout mice generate conflicting data on the role of IL-6 on hepatocyte proliferation and liver regeneration [
      • Sakamoto T.
      • Liu Z.
      • Murase N.
      • Ezure T.
      • Yokomuro S.
      • Poli V.
      • et al.
      Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy.
      ,
      • Blindenbacher A.
      • Wang X.
      • Langer I.
      • Savino R.
      • Terracciano L.
      • Heim M.H.
      Interleukin 6 is important for survival after partial hepatectomy in mice.
      ,
      • Sun R.
      • Jaruga B.
      • Kulkarni S.
      • Sun H.
      • Gao B.
      IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: regulation by SOCS3.
      ,
      • Wuestefeld T.
      • Klein C.
      • Streetz K.L.
      • Betz U.
      • Lauber J.
      • Buer J.
      • et al.
      Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration.
      ]. In contrast, the reports on the role of STAT3 in liver regeneration are consistent. For example, inhibition of hepatic STAT3, mediated through STAT3 or gp130 deletion, reduced liver regeneration after partial hepatectomy [
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ,
      • Li W.
      • Liang X.
      • Kellendonk C.
      • Poli V.
      • Taub R.
      STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration.
      ,
      • Dierssen U.
      • Beraza N.
      • Lutz H.H.
      • Liedtke C.
      • Ernst M.
      • Wasmuth H.E.
      • et al.
      Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration.
      ,
      • Moh A.
      • Iwamoto Y.
      • Chai G.X.
      • Zhang S.S.
      • Kano A.
      • Yang D.D.
      • et al.
      Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery.
      ]. Conversely, augmentation of hepatic STAT3, induced via either SOCS3 deletion or IL-22 overexpression, accelerated liver regeneration [
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ,
      • Riehle K.J.
      • Campbell J.S.
      • McMahan R.S.
      • Johnson M.M.
      • Beyer R.P.
      • Bammler T.K.
      • et al.
      Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3.
      ].
      Whereas STAT3 is critical for liver regeneration, STAT1 activation plays a role in inhibiting liver regeneration as STAT1 deletion accelerated liver regeneration and diminished the inhibitory effect of poly I:C treatment on liver regeneration in the partial hepatectomy model [
      • Sun R.
      • Park O.
      • Horiguchi N.
      • Kulkarni S.
      • Jeong W.I.
      • Sun H.Y.
      • et al.
      STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
      ,
      • Sun R.
      • Gao B.
      Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma).
      ]. Furthermore, in vitro IFN-γ treatment induced cell cycle arrest and apoptosis in wild-type but not in STAT1-deficient hepatocytes [
      • Sun R.
      • Park O.
      • Horiguchi N.
      • Kulkarni S.
      • Jeong W.I.
      • Sun H.Y.
      • et al.
      STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
      ]. Recently, we demonstrated that hepatic STAT1 levels were highly upregulated in the double mutant mice with STAT3 deletion in myeloid cells and hepatocytes, and this STAT1 upregulation correlated with impaired liver regeneration and increased mortality in these mice following partial hepatectomy [
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ]. The additional deletion of STAT1 in these double mutant mice restored liver regeneration and abolished the mortality induced by partial hepatectomy, providing conclusive evidence that high STAT1 levels in the liver attenuate liver regeneration [
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ]. Interestingly, many viral hepatitis patients have high levels of hepatic STAT1 expression that positively correlate with liver injury but negatively correlate with hepatocyte proliferation [
      • Sun R.
      • Park O.
      • Horiguchi N.
      • Kulkarni S.
      • Jeong W.I.
      • Sun H.Y.
      • et al.
      STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
      ,
      • Radaeva S.
      • Jaruga B.
      • Kim W.H.
      • Heller T.
      • Liang T.J.
      • Gao B.
      Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C.
      ]. Thus, in patients with viral hepatitis, such enhanced STAT1 activation likely plays a beneficial role in eliminating HCV in the early stage of infection. However, when HCV infection fails to resolve and becomes persistent, STAT1 activation likely not only contributes to hepatocelluar damage, but also impedes liver regeneration by inhibiting hepatocyte proliferation.

      Diverse functions of STAT proteins in liver inflammation

      Figure thumbnail fx3

      STAT1: a pro-inflammatory signal

      Mice with a global deletion of STAT1 are resistant to liver injury and inflammation induced by Con A or LPS plus D-galactosamine [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Siebler J.
      • Wirtz S.
      • Klein S.
      • Protschka M.
      • Blessing M.
      • Galle P.R.
      • et al.
      A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
      ,
      • Kim W.H.
      • Hong F.
      • Radaeva S.
      • Jaruga B.
      • Fan S.
      • Gao B.
      STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
      ], suggesting that STAT1 plays a pro-inflammatory role in the pathogenesis of liver disease. Accumulating evidence suggests that STAT1 activation in both liver parenchymal and non-parenchymal cells exacerbates liver inflammation and injury. In hepatocytes, STAT1 is predominantly activated by IFN-γ, and to a lesser extent by IFN-α/β and IL-27 [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Siebler J.
      • Wirtz S.
      • Frenzel C.
      • Schuchmann M.
      • Lohse A.W.
      • Galle P.R.
      • et al.
      Cutting edge: a key pathogenic role of IL-27 in T cell-mediated hepatitis.
      ]. IFN-γ activation of STAT1 directly induces hepatocyte apoptosis, resulting in apoptosis-associated liver inflammation [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Siebler J.
      • Wirtz S.
      • Klein S.
      • Protschka M.
      • Blessing M.
      • Galle P.R.
      • et al.
      A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
      ,
      • Kim W.H.
      • Hong F.
      • Radaeva S.
      • Jaruga B.
      • Fan S.
      • Gao B.
      STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
      ]. In addition, IFN-γ promotes liver inflammation by inducing the expression of chemokines and the adhesion molecules VCAM-1 and ICAM-1 in hepatocytes, sinusoidal endothelial cells, and Kupffer cells in an STAT1-dependent manner [
      • Jaruga B.
      • Hong F.
      • Kim W.H.
      • Gao B.
      IFN-{gamma}/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1.
      ]. Finally, transgenic mice with overexpression of STAT1 in T cells are more susceptible to Con A-induced hepatitis [
      • Siebler J.
      • Wirtz S.
      • Klein S.
      • Protschka M.
      • Blessing M.
      • Galle P.R.
      • et al.
      A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
      ], suggesting that STAT1 in T cells acts as a pro-inflammatory signal to promote liver inflammation in this model.

      Hepatocyte STAT3: an anti- and pro-inflammatory signal

      STAT3 activation in hepatocytes occurs following stimulation with IL-22, IL-6, and IL-6 family cytokines and acts as an anti-inflammatory signal to suppress liver inflammation under most conditions [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Zenewicz L.A.
      • Yancopoulos G.D.
      • Valenzuela D.M.
      • Murphy A.J.
      • Karow M.
      • Flavell R.A.
      Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
      ,
      • Kroy D.C.
      • Beraza N.
      • Tschaharganeh D.F.
      • Sander L.E.
      • Erschfeld S.
      • Giebeler A.
      • et al.
      Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice.
      ,
      • Sakamori R.
      • Takehara T.
      • Ohnishi C.
      • Tatsumi T.
      • Ohkawa K.
      • Takeda K.
      • et al.
      Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice.
      ,
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ], but could also promote liver inflammation in some models of liver injury. For example, disruption of STAT3 in hepatocytes markedly increased liver injury and inflammation after chronic CCl4 administration [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ], but decreased liver inflammation after acute CCl4 injection [
      • Horiguchi N.
      • Lafdil F.
      • Miller A.M.
      • Park O.
      • Wang H.
      • Rajesh M.
      • et al.
      Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice.
      ], suggesting that hepatocyte STAT3 can act as both an anti- and pro-inflammatory signal depending on the liver injury models. The anti-inflammatory effects of hepatocyte STAT3 are most likely due to the prevention of hepatocellular damage and the subsequent reduction of necrosis-associated inflammation. Moreover, hepatocyte STAT3 can suppress the pro-inflammatory functions of STAT1 in liver injury models with strong STAT1 activation, such as the Con A- and LPS-induced hepatitis models [
      • Hong F.
      • Jaruga B.
      • Kim W.H.
      • Radaeva S.
      • El-Assal O.N.
      • Tian Z.
      • et al.
      Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
      ,
      • Sakamori R.
      • Takehara T.
      • Ohnishi C.
      • Tatsumi T.
      • Ohkawa K.
      • Takeda K.
      • et al.
      Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice.
      ]. The pro-inflammatory effects of hepatocyte STAT3 are thought to be mediated through the induction of acute phase proteins and chemokines in situations with weak STAT1 activation, such as the acute CCl4- and alcohol-induced liver injury models [
      • Horiguchi N.
      • Lafdil F.
      • Miller A.M.
      • Park O.
      • Wang H.
      • Rajesh M.
      • et al.
      Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice.
      ,
      • Horiguchi N.
      • Wang L.
      • Mukhopadhyay P.
      • Park O.
      • Jeong W.I.
      • Lafdil F.
      • et al.
      Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
      ].

      Myeloid cell STAT3: an anti-inflammatory signal

      STAT3 is a key downstream signaling protein of the anti-inflammatory cytokine IL-10 in macrophages [
      • Murray P.J.
      Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response.
      ], and accumulating evidence also confirms that STAT3 in macrophages and other myeloid cells acts as a critical anti-inflammatory signal to control liver inflammation. Myeloid-specific STAT3-deficient mice, in which STAT3 is deleted in myeloid linage cells including Kupffer cells/macrophages, are prone to a higher degree of liver inflammation in murine models of liver injury induced by a variety of hepatic toxins [
      • Lafdil F.
      • Wang H.
      • Park O.
      • Zhang W.
      • Moritoki Y.
      • Yin S.
      • et al.
      Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
      ,
      • Horiguchi N.
      • Lafdil F.
      • Miller A.M.
      • Park O.
      • Wang H.
      • Rajesh M.
      • et al.
      Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice.
      ,
      • Horiguchi N.
      • Wang L.
      • Mukhopadhyay P.
      • Park O.
      • Jeong W.I.
      • Lafdil F.
      • et al.
      Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
      ,
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ]. Also, STAT3-deficient Kupffer cells produced higher levels of TNF-α after in vitro LPS stimulation compared with wild type Kupffer cells [
      • Horiguchi N.
      • Wang L.
      • Mukhopadhyay P.
      • Park O.
      • Jeong W.I.
      • Lafdil F.
      • et al.
      Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
      ]. These results suggest that STAT3 activation in macrophages inhibits pro-inflammatory cytokine production. At present, the mechanisms underlying the anti-inflammatory effects of STAT3 in macrophages remain largely unknown. One potential mechanism is that STAT3 mediates the inhibition of pro-inflammatory STAT1 signaling. Consistent with this, STAT1 activation is markedly upregulated in Kupffer cells/macrophages in myeloid-specific STAT3 deficient mice, the additional deletion of STAT1 in these mice reduced both hepatic and systemic inflammation in Con A-induced hepatitis and partial hepatectomy models [
      • Lafdil F.
      • Wang H.
      • Park O.
      • Zhang W.
      • Moritoki Y.
      • Yin S.
      • et al.
      Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
      ,
      • Wang H.
      • Park O.
      • Lafdil F.
      • Shen K.
      • Horiguchi N.
      • Yin S.
      • et al.
      Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
      ].

      T cell STAT3: an anti- and pro-inflammatory signal

      In T cells, STAT3 activation has been shown to promote or reduce liver inflammation depending on the liver injury models being studied. For example, T cell-specific STAT3-deficient mice are resistant to Con A-induced liver inflammation and exhibit reduced IL-17 production [
      • Lafdil F.
      • Wang H.
      • Park O.
      • Zhang W.
      • Moritoki Y.
      • Yin S.
      • et al.
      Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
      ]. However, inhibition of STAT3 in T cells via SOCS3 overexpression accelerated acetaminophen hepatotoxicity due to the induction of IFN-γ and TNF-α production [
      • Numata K.
      • Kubo M.
      • Watanabe H.
      • Takagi K.
      • Mizuta H.
      • Okada S.
      • et al.
      Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity.
      ]. It is probable that STAT3 activation in T cells induces the expression of the RORγt and RORα transcription factors, which promote differentiation towards a Th17 phenotype. In turn, Th17 cell-derived IL-17 production could contribute to liver inflammation. However, STAT3 activation in T cells may also inhibit STAT1 signaling and prevent a polarization toward a Th1 phenotype, thus reducing IFN-γ production and inhibiting liver inflammation.
      Taken together, these findings suggest that the role of STAT3 in liver inflammation is complex. While STAT1 promotes inflammation under many conditions, activation of the STAT3 signaling pathway in hepatocytes generally leads to anti-inflammatory responses by preventing hepatocellular damage and inhibiting the STAT1 signaling pathway. However, activation of STAT3 in hepatocytes may also enhance liver inflammation via the induction of acute phase proteins, chemokines, and chemokine receptors in several models. In myeloid cells, STAT3 activation is a key anti-inflammatory signal for the control of liver inflammation. Finally, in T cells, STAT3 can act as either a pro- or anti-inflammatory signal in regulating liver inflammation depending on the liver injury models being studied.

      STAT4: a pro- and anti-inflammatory signal

      In general, STAT4, which is activated by IL-12 and IFN-α/β in several types of immune cells, is important in generating inflammation during protective immune responses and immune-mediated diseases [
      • Kaplan M.H.
      STAT4: a critical regulator of inflammation in vivo.
      ]. Overexpression of IL-12 in the liver by hydrodynamic injection of IL-12 cDNA resulted in liver injury [
      • Rodriguez-Galan M.C.
      • Reynolds D.
      • Correa S.G.
      • Iribarren P.
      • Watanabe M.
      • Young H.A.
      Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity.
      ]. Conversely, deletion of IL-12 suppressed liver inflammation in dominant negative TGF-β receptor transgenic mice [
      • Yoshida K.
      • Yang G.X.
      • Zhang W.
      • Tsuda M.
      • Tsuneyama K.
      • Moritoki Y.
      • et al.
      Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice.
      ] and in the Con A-induced hepatitis [
      • Zhu R.
      • Diem S.
      • Araujo L.M.
      • Aumeunier A.
      • Denizeau J.
      • Philadelphe E.
      • et al.
      The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis.
      ]. Also, IL-12 treatment has been shown to inhibit liver tumor growth in several animal models through the induction of a pro-inflammatory response [
      • Chang C.J.
      • Chen Y.H.
      • Huang K.W.
      • Cheng H.W.
      • Chan S.F.
      • Tai K.F.
      • et al.
      Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors.
      ,
      • Harada N.
      • Shimada M.
      • Okano S.
      • Suehiro T.
      • Soejima Y.
      • Tomita Y.
      • et al.
      IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice.
      ]. These findings suggest that IL-12 acts as a pro-inflammatory cytokine that induces liver injury and inhibits liver tumor growth by activating NK and NKT cells to produce IFN-γ [
      • Subleski J.J.
      • Hall V.L.
      • Back T.C.
      • Ortaldo J.R.
      • Wiltrout R.H.
      Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver.
      ]. Despite the fact that the functions of IL-12 in liver injury and inflammation have been extensively investigated, the role of STAT4 in the pathogenesis of liver diseases remains largely unknown. One study reported that STAT4-deficient mice were resistant to hepatic ischemia/reperfusion injury [
      • Shen X.D.
      • Ke B.
      • Zhai Y.
      • Gao F.
      • Anselmo D.
      • Lassman C.R.
      • et al.
      Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice. HO-1 dependence of Stat4 disruption-mediated cytoprotection.
      ]; however, another study showed that STAT4-deficient and wild-type mice had equal liver injury after ischemia/reperfusion [
      • Kato A.
      • Graul-Layman A.
      • Edwards M.J.
      • Lentsch A.B.
      Promotion of hepatic ischemia/reperfusion injury by IL-12 is independent of STAT4.
      ]. The reason for the discrepancy between these two studies is not clear and further studies are required to clarify the roles of STAT4 in liver injury and inflammation.

      STAT6: a pro- and anti-inflammatory signal

      Both IL-4 and IL-13 strongly induce STAT6 activation in the liver and likely play complex roles in controlling liver injury and inflammation. IL-4 has been shown to have pro-inflammatory/pathogenic effects via activation of STAT6 in a wide variety of liver injury models [
      • Jaruga B.
      • Hong F.
      • Sun R.
      • Radaeva S.
      • Gao B.
      Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
      ,
      • Higuchi S.
      • Kobayashi M.
      • Yoshikawa Y.
      • Tsuneyama K.
      • Fukami T.
      • Nakajima M.
      • et al.
      IL-4 mediates dicloxacillin-induced liver injury in mice.
      ,
      • Njoku D.B.
      • Li Z.
      • Washington N.D.
      • Mellerson J.L.
      • Talor M.V.
      • Sharma R.
      • et al.
      Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.
      ,
      • Douglas D.B.
      • Beiting D.P.
      • Loftus J.P.
      • Appleton J.A.
      • Bliss S.K.
      Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection.
      ]. For example, IL-4- or STAT6-deficient mice were resistant to Con A-induced liver injury and inflammation [
      • Jaruga B.
      • Hong F.
      • Sun R.
      • Radaeva S.
      • Gao B.
      Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
      ]. Such detrimental effect of IL-4 in this model is likely mediated by upregulating eotaxins and IL-5 expression in the liver [
      • Jaruga B.
      • Hong F.
      • Sun R.
      • Radaeva S.
      • Gao B.
      Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
      ]. In contrast, IL-4-deficient mice were more susceptible to acetaminophen-induced liver injury, which was corrected by administration of recombinant IL-4 [
      • Ryan P.B.M.
      • Korrapati M.C.
      • Proctor W.R.
      • Vasquez R.V.
      • Yee S.B.
      • Quinn T.D.
      • et al.
      Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
      ]. The hepatoprotective function of IL-4 in drug-induced injury is mediated, at least in part, via the upregulation of hepatic glutathione synthesis [
      • Ryan P.B.M.
      • Korrapati M.C.
      • Proctor W.R.
      • Vasquez R.V.
      • Yee S.B.
      • Quinn T.D.
      • et al.
      Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
      ]. In addition, both IL-4 and IL-13 has also been shown to be protective against ischemia/reperfusion liver injury [
      • Kato A.
      • Yoshidome H.
      • Edwards M.J.
      • Lentsch A.B.
      Reduced hepatic ischemia/reperfusion injury by IL-4: potential anti-inflammatory role of STAT6.
      ,
      • Kato A.
      • Okaya T.
      • Lentsch A.B.
      Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury.
      ,
      • Yoshidome H.
      • Kato A.
      • Miyazaki M.
      • Edwards M.J.
      • Lentsch A.B.
      IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion.
      ,
      • Ke B.
      • Shen X.D.
      • Gao F.
      • Busuttil R.W.
      • Kupiec-Weglinski J.W.
      Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection.
      ,
      • Cao Z.
      • Yuan Y.
      • Jeyabalan G.
      • Du Q.
      • Tsung A.
      • Geller D.A.
      • et al.
      Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor.
      ], which was hypothesized to be mediated through STAT6 activation and subsequent inhibition of inflammation and protection against hepatocyte and endothelial cell damage [
      • Kato A.
      • Yoshidome H.
      • Edwards M.J.
      • Lentsch A.B.
      Reduced hepatic ischemia/reperfusion injury by IL-4: potential anti-inflammatory role of STAT6.
      ,
      • Kato A.
      • Okaya T.
      • Lentsch A.B.
      Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury.
      ,
      • Yoshidome H.
      • Kato A.
      • Miyazaki M.
      • Edwards M.J.
      • Lentsch A.B.
      IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion.
      ,
      • Ke B.
      • Shen X.D.
      • Gao F.
      • Busuttil R.W.
      • Kupiec-Weglinski J.W.
      Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection.
      ,
      • Cao Z.
      • Yuan Y.
      • Jeyabalan G.
      • Du Q.
      • Tsung A.
      • Geller D.A.
      • et al.
      Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor.
      ].

      STATs and liver cancer

      STAT1: a tumor suppressor

      IFN-activated STAT1 is a well-documented tumor suppressor that induces cell cycle arrest and apoptosis in various types of tumors [
      • Adámková L.
      • Kovarík J.
      Transcription protein STAT1: biology and relation to cancer.
      ]. Consistent with this, STAT1-deficient mice are more susceptible to the development of methylcholanthrene-induced tumors and N-nitroso-N-methylurea-induced thymic tumors [
      • Kaplan D.H.
      • Shankaran V.
      • Dighe A.S.
      • Stockert E.
      • Aguet M.
      • Old L.J.
      • et al.
      Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.
      ,
      • Lee C.K.
      • Smith E.
      • Gimeno R.
      • Gertner R.
      • Levy D.E.
      STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma.
      ]; however, they exhibit similar susceptibility to liver tumors induced by a single injection of DEN compared with wild-type mice [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ]. The negligible role of STAT1 in this DEN-induced liver tumor model may be because this model is associated with minimal STAT1 activation [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ]. Since STAT1 protein expression and phosphorylation are highly elevated in viral hepatitis [
      • Sun R.
      • Park O.
      • Horiguchi N.
      • Kulkarni S.
      • Jeong W.I.
      • Sun H.Y.
      • et al.
      STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
      ,
      • Radaeva S.
      • Jaruga B.
      • Kim W.H.
      • Heller T.
      • Liang T.J.
      • Gao B.
      Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C.
      ], STAT1 likely plays a role in preventing HCC development in patients with chronic viral hepatitis. Indeed, STAT1 gene polymorphisms with homozygous genotypes at rs867637, rs3771300, and rs2280235 in patients with viral hepatitis have been found to be associated with an increased risk for developing HCC [
      • Zhu Z.Z.
      • Di J.Z.
      • Gu W.Y.
      • Cong W.M.
      • Gawron A.
      • Wang Y.
      • et al.
      Association of genetic polymorphisms in STAT1 gene with increased risk of hepatocellular carcinoma.
      ]. In addition, a combination therapy of 5-fluorouracil with IFN-α, which activates STAT1 in liver cells, displayed promising results for the treatment of advanced HCC with tumor thrombi in the major portal branches [
      • Nagano H.
      Treatment of advanced hepatocellular carcinoma: intraarterial infusion chemotherapy combined with interferon.
      ].

      STAT3: hepatoprotective versus oncogenic functions

      It is generally believed that STAT3 activation contributes to the development and progression of many types of cancer, including liver cancer [
      • Haura E.B.
      • Turkson J.
      • Jove R.
      Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer.
      ,
      • Yu H.
      • Jove R.
      The STATs of cancer – new molecular targets come of age.
      ]. The oncogenic effect of STAT3 in tumor cells is mediated by the upregulation of a diverse array of genes that promote tumor cell survival and proliferation, and many mediators that suppress anti-tumor immunity [
      • Haura E.B.
      • Turkson J.
      • Jove R.
      Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer.
      ,
      • Yu H.
      • Jove R.
      The STATs of cancer – new molecular targets come of age.
      ]. The important role of STAT3 in promoting liver tumorigenesis has also been well documented [
      • Wang H.
      • Lafdil F.
      • Kong X.
      • Gao B.
      Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target.
      ,
      • He G.
      • Karin M.
      NF-kappaB and STAT3 – key players in liver inflammation and cancer.
      ]. First, STAT3 protein expression and phosphorylation are elevated in human HCC tissue samples compared with surrounding non-neoplastic tissue and normal healthy liver tissue samples [
      • Lin L.
      • Amin R.
      • Gallicano G.I.
      • Glasgow E.
      • Jogunoori W.
      • Jessup J.M.
      • et al.
      The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.
      ,
      • Calvisi D.F.
      • Ladu S.
      • Gorden A.
      • Farina M.
      • Conner E.A.
      • Lee J.S.
      • et al.
      Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.
      ]. In human HCC, the increased STAT3 activation is likely due to persistent stimulation from upstream signals such as the oncogenes and cytokines such as IL-22 [
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ,
      • Jiang R.T.Z.
      • Deng L.
      • Chen Y.
      • Xia Y.
      • Gao Y.
      • Wang X.
      • et al.
      Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.
      ], or due to the blockade of inhibitory pathways, such as the methylation-mediated silencing of SOCS proteins [
      • Yoshikawa H.
      • Matsubara K.
      • Qian G.S.
      • Jackson P.
      • Groopman J.D.
      • Manning J.E.
      • et al.
      SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.
      ,
      • Niwa Y.
      • Kanda H.
      • Shikauchi Y.
      • Saiura A.
      • Matsubara K.
      • Kitagawa T.
      • et al.
      Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.
      ]. Second, inhibition of STAT3 activation by STAT3 inhibitors [
      • Lin L.
      • Amin R.
      • Gallicano G.I.
      • Glasgow E.
      • Jogunoori W.
      • Jessup J.M.
      • et al.
      The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.
      ], miR-637 [
      • Zhang J.F.
      • He M.L.
      • Fu W.M.
      • Wang H.
      • Chen L.Z.
      • Zhu X.
      • et al.
      Primate-specific miRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting stat3 signaling.
      ], or sunitinib [
      • Avella D.M.
      • Li G.
      • Schell T.D.
      • Liu D.
      • Shao-Min Zhang S.
      • et al.
      Regression of established hepatocellular carcinoma is induced by chemo-immunotherapy in an orthotopic murine model.
      ] reduced liver tumor cell growth in vitro or in vivo; while activation of STAT3 by HCV core protein [
      • Machida K.
      • Tsukamoto H.
      • Liu J.C.
      • Han Y.P.
      • Govindarajan S.
      • Lai M.M.
      • et al.
      C-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair.
      ] or HBX protein [
      • Wang C.
      • Yang W.
      • Yan H.X.
      • Luo T.
      • Zhang J.
      • Tang L.
      • et al.
      HBx induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treated HBx transgenic mice.
      ] promoted HCC development. Third, genetic deletion of IL-6 resulted in a reduction of STAT3 activation and the prevention of diethylnitrosamine (DEN)-induced HCC development in lean [
      • Naugler W.E.
      • Sakurai T.
      • Kim S.
      • Maeda S.
      • Kim K.
      • Elsharkawy A.M.
      • et al.
      Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
      ] and obese mice [
      • Park E.J.
      • Lee J.H.
      • Yu G.Y.
      • He G.
      • Ali S.R.
      • Holzer R.G.
      • et al.
      Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
      ]. In contrast, augmentation of liver STAT3 activation mediated through IL-22 overexpression or the conditional deletion of the SHP-2 or SOCS3 in hepatocytes increased DEN-induced HCC development [
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ,
      • Riehle K.J.
      • Campbell J.S.
      • McMahan R.S.
      • Johnson M.M.
      • Beyer R.P.
      • Bammler T.K.
      • et al.
      Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3.
      ,
      • Bard-Chapeau E.A.
      • Li S.
      • Ding J.
      • Zhang S.S.
      • Zhu H.H.
      • Princen F.
      • et al.
      Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis.
      ]. Finally, conditional deletion of STAT3 in hepatocytes reduced DEN-induced HCC development in wild type mice [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ,
      • He G.
      • Yu G.Y.
      • Temkin V.
      • Ogata H.
      • Kuntzen C.
      • Sakurai T.
      • et al.
      Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
      ] and in liver-specific SHP-2 knockout mice [
      • Bard-Chapeau E.A.
      • Li S.
      • Ding J.
      • Zhang S.S.
      • Zhu H.H.
      • Princen F.
      • et al.
      Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis.
      ].
      It is well known that more than 80% of human HCC develop following chronic liver injury, inflammation, and cirrhosis. However, the DEN model is associated with minimal liver inflammation and injury. Thus, this model may not be an ideal one to investigate the molecular mechanisms of human HCC development caused by chronic liver injury and inflammation. Instead, we utilized a model of chronic liver injury induced by repeated injection of CCl4 and found that deletion of hepatic STAT3 exacerbated CCl4-induced liver inflammation and fibrosis and increased the incidence of HCC development [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ]. Collectively, hepatic STAT3 accelerates liver tumor development induced by a single injection of DEN, but prevents liver tumor development in the murine model of chronic CCl4 administration [
      • Wang H.
      • Lafdil F.
      • Wang L.
      • Park O.
      • Yin S.
      • Niu J.
      • et al.
      Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
      ]. These dual roles of STAT3 in liver tumorigenesis are summarized in Fig. 3. Under the conditions of persistent inflammatory stress and liver injury, STAT3 acts as a hepatoprotective signal to prevent hepatic damage and fibrosis, consequently suppressing injury- and inflammation-driven liver tumor initiation. However, once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor that promotes tumorigenesis. Interestingly, both tumor suppressive and oncogenic effects of STAT3 were also recently reported in a murine model of liver tumors [
      • Schneller D.
      • Machat G.
      • Sousek A.
      • Proell V.
      • van Zijl F.
      • Zulehner G.
      • et al.
      P19(ARF)/p14(ARF) controls oncogenic functions of signal transducer and activator of transcription 3 in hepatocellular carcinoma.
      ,
      • Calvisi D.F.
      Dr. Jekyll, Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer.
      ]. In this model, overexpression of a constitutively active form of STAT3 promoted liver tumorigenesis in the presence of the tumor suppressor p14ARF (the human homolog of p19ARF). However, in the absence of p14ARF, constitutively active STAT3 induced tumor suppression, likely via the activation of an alternative group of STAT3-specific target genes with anti-oncogenic activity.
      Figure thumbnail gr3
      Fig. 3Hepatoprotective versus oncogenic functions of STAT3. During chronic liver injury, steatosis, and inflammation, IL-6, IL-6 family cytokines, and IL-22 induce STAT3 activation, leading to the upregulation of a variety of anti-apoptotic, anti-oxidative, and anti-steatogenic proteins in hepatocytes that prevent liver injury and inhibit injury-associated HCC initiation. IL-22 may have therapeutic potential in the treatment of liver failure (e.g. acute alcoholic hepatitis) and fatty liver disease. In contrast, during end-stage liver cirrhosis and liver cancer, STAT3 activation promotes tumor cell survival and proliferation and therefore HCC progression. Thus, STAT3 inhibitors may have therapeutic potential in the treatment of HCC.

      STAT5a/b: a tumor suppressor and hepatoprotective factor

      Constitutively activated STAT5 has been observed in a wide variety of tumors, including HCC [
      • Ferbeyre G.
      • Moriggl R.
      The role of Stat5 transcription factors as tumor suppressors or oncogenes.
      ]. Many studies suggest that STAT5 activation plays an important role in promoting tumorigenesis via the upregulation of anti-apoptotic, cell proliferative, and invasion and metastasis-related genes [
      • Ferbeyre G.
      • Moriggl R.
      The role of Stat5 transcription factors as tumor suppressors or oncogenes.
      ]. However, recent studies have demonstrated that hepatic growth hormone-mediated STAT5 activation plays a hepatoprotective role in preventing the development of HCC. First, liver-specific STAT5 knockout mice are more susceptible to chronic CCl4-induced liver fibrosis and HCC development [
      • Hosui A.
      • Kimura A.
      • Yamaji D.
      • Zhu B.M.
      • Na R.
      • Hennighausen L.
      Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation.
      ]. Second, the combined deletion of STAT5 and the glucocorticoid receptor in hepatocytes results in severe metabolic liver disease and spontaneous hepatic tumorigenesis [
      • Mueller K.M.
      • Kornfeld J.W.
      • Friedbichler K.
      • Blaas L.
      • Egger G.
      • Esterbauer H.
      • et al.
      Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
      ]. Finally, the conditional deletion of hepatic STAT5 accelerated inflammatory liver cancer caused by hyperactivated growth hormone signaling despite the observed reductions in chronic inflammation [
      • Friedbichler K.T.M.
      • Mueller K.M.
      • Schlederer M.
      • Kornfeld J.W.
      • Terracciano L.M.
      • Kozlov A.V.
      • et al.
      Growth hormone-induced STAT5 signaling causes gigantism, inflammation and premature death but protects mice from aggressive liver cancer.
      ]. These findings suggest that STAT5 acts as a tumor suppressor in liver tumorigenesis via its anti-steatogenic and hepatoprotective effects and through the upregulation of the cell cycle inhibitors Cdkn2b and Cdkn1a [
      • Mueller K.M.
      • Kornfeld J.W.
      • Friedbichler K.
      • Blaas L.
      • Egger G.
      • Esterbauer H.
      • et al.
      Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
      ,
      • Friedbichler K.T.M.
      • Mueller K.M.
      • Schlederer M.
      • Kornfeld J.W.
      • Terracciano L.M.
      • Kozlov A.V.
      • et al.
      Growth hormone-induced STAT5 signaling causes gigantism, inflammation and premature death but protects mice from aggressive liver cancer.
      ,
      • Yu J.H.
      • Zhu B.M.
      • Wickre M.
      • Riedlinger G.
      • Chen W.
      • Hosui A.
      • et al.
      The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B negatively regulate cell proliferation through the activation of cyclin-dependent kinase inhibitor 2b (Cdkn2b) and Cdkn1a expression.
      ]. However, it is not clear whether STAT5, similar to STAT3, can also promote HCC cell proliferation once HCC cells have developed.

      STATs as potential clinical targets for the treatment of liver diseases

      Although STATs have been identified as the key regulators of hepatic anti-viral responses, inflammation, and tumorigenesis, the translation of them as therapeutic targets for the treatment of liver diseases has lagged behind. Here, we discuss several candidates of STATs as potential therapeutic targets.

      STAT1–STAT2 activators

      Activation of STAT1 and STAT2 in hepatocytes plays key roles in the IFN-α-mediated anti-viral response against HCV infections. Enhancing activation of these STATs could be an attractive strategy to improve the efficiency of IFN-α therapy for the treatment of HCV. Indeed, a recent study showed that treatment with S-adenosyl methionine, which potentiates STAT1 activation, improved the early viral kinetics and increases IFN-stimulated gene induction in non-responders treated with peg-IFN and ribavirin [
      • Feld J.J.
      • Modi A.A.
      • El-Diwany R.
      • Rotman Y.
      • Thomas E.
      • Ahlenstiel G.
      • et al.
      S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders.
      ].

      STAT3 inhibitors

      Although STAT3 inhibitors have been actively investigated in preclinical studies for the treatment of HCC and other various types of cancer [
      • Page B.D.
      • Ball D.P.
      • Gunning P.T.
      Signal transducer and activator of transcription 3 inhibitors: a patent review.
      ], they have not yet been tested in HCC patients. Sorafenib is a safe and effective drug approved for the treatment of advanced HCC [
      • Iavarone M.
      • Cabibbo G.
      • Piscaglia F.
      • Zavaglia C.
      • Grieco A.
      • Villa E.
      • et al.
      Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
      ,
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Villanueva A.
      • Llovet J.M.
      Targeted therapies for hepatocellular carcinoma.
      ]. It was originally developed as a small molecule inhibitor of the VEGFR and PDGFR tyrosine kinases and the Raf/Mek/Erk pathways [
      • Siegel A.B.
      • Olsen S.K.
      • Magun A.
      • Brown Jr., R.S.
      Sorafenib: where do we go from here?.
      ]. However, it is now known that sorafenib also inhibits STAT3 in liver cancer cells by inducing the activation of protein tyrosine phosphatases [
      • Blechacz B.R.
      • Smoot R.L.
      • Bronk S.F.
      • Werneburg N.W.
      • Sirica A.E.
      • Gores G.J.
      Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2.
      ,
      • Tai W.T.
      • Cheng A.L.
      • Shiau C.W.
      • Huang H.P.
      • Huang J.W.
      • Chen P.J.
      • et al.
      Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.
      ]. Interestingly, a recent study showed that SC-1, a sorafenib analog lacking inhibitory activity toward the VEGFR and PDGFR tyrosine kinases and the Raf/Mek/Erk pathways but retaining inhibitory activity against STAT3, was as potent as sorafenib in the induction of cell cycle arrest and apoptosis of human HCC cell lines in vitro [
      • Tai W.T.
      • Cheng A.L.
      • Shiau C.W.
      • Huang H.P.
      • Huang J.W.
      • Chen P.J.
      • et al.
      Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.
      ]. This study suggests that STAT3 inhibition is predominately responsible for the sorafenib-mediated anti-tumor effects observed on HCC cells, whereas the inhibition of the VEGFR and PDGFR tyrosine kinases and the Raf/Mek/Erk pathways plays a minor role [
      • Tai W.T.
      • Cheng A.L.
      • Shiau C.W.
      • Huang H.P.
      • Huang J.W.
      • Chen P.J.
      • et al.
      Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.
      ,
      • Rosmorduc O.
      • Desbois-Mouthon C.
      Targeting STAT3 in hepatocellular carcinoma: Sorafenib again.
      ]. Thus, clinical trials examining specific STAT3 inhibitors for HCC patients are warranted.

      STAT3 activator

      IL-22, which activates STAT3 in hepatocytes but not in immune cells, is currently under development for the treatment of human fulminant hepatitis, liver failure, and fatty liver disease. This is based on the facts that IL-22 promotes hepatocyte survival and proliferation [
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ,
      • Radaeva S.
      • Sun R.
      • Pan H.N.
      • Hong F.
      • Gao B.
      Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation.
      ], and ameliorates steatosis [
      • Ki S.H.
      • Park O.
      • Zheng M.
      • Morales-Ibanez O.
      • Kolls J.K.
      • Bataller R.
      • et al.
      Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.
      ,
      • Yang L.
      • Zhang Y.
      • Wang L.
      • Fan F.
      • Zhu L.
      • Li Z.
      • et al.
      Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22.
      ] with the added benefit of antimicrobial effects and potentially few side effects. Since IL-22 also promotes liver tumor cell survival [
      • Park O.
      • Wang H.
      • Weng H.
      • Feigenbaum L.
      • Li H.
      • Yin S.
      • et al.
      In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
      ,
      • Radaeva S.
      • Sun R.
      • Pan H.N.
      • Hong F.
      • Gao B.
      Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation.
      ], the application of IL-22 should not be used in patients with pre-cancerous cirrhosis or liver cancer.

      Conclusions

      In summary, studies from the last decade from animal models suggest that multiple STATs collectively exhibit diverse and complex biological functions in regulating hepatic anti-viral responses, inflammation, and tumorigenesis. These findings have markedly enhanced our understanding of liver disease pathophysiology and treatments, but translation of these basic research findings into new therapeutic modalities for managing human liver diseases has been modest. We hope this review article will stimulate translational and clinical research on these topics in the near future.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      The underlying research reported in this study was funded by the NIH Institutes of Health.

      Financial support

      The work described here from Dr. Bin Gao’s laboratory was supported by the intramural program of the NIAAA, NIH.

      References

        • Darnell Jr., J.E.
        • Kerr I.M.
        • Stark G.R.
        Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
        Science. 1994; 264: 1415-1421
        • Schindler C.
        Cytokines and JAK–STAT signaling.
        Exp Cell Res. 1999; 253: 7-14
        • Gao B.
        Cytokines, STATs and liver disease.
        Cell Mol Immunol. 2005; 2: 92-100
        • Ruff-Jamison S.
        • Chen K.
        • Cohen S.
        Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei.
        Science. 1993; 261: 1733-1736
        • Machida K.
        • Tsukamoto H.
        • Liu J.C.
        • Han Y.P.
        • Govindarajan S.
        • Lai M.M.
        • et al.
        C-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair.
        Hepatology. 2010; 52: 480-492
        • Wormald S.
        • Hilton D.J.
        Inhibitors of cytokine signal transduction.
        J Biol Chem. 2004; 279: 821-824
        • Alexander W.S.
        • Hilton D.J.
        The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response.
        Annu Rev Immunol. 2004; 22: 503-529
        • Hong F.
        • Jaruga B.
        • Kim W.H.
        • Radaeva S.
        • El-Assal O.N.
        • Tian Z.
        • et al.
        Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
        J Clin Invest. 2002; 110: 1503-1513
        • Croker B.A.
        • Krebs D.L.
        • Zhang J.G.
        • Wormald S.
        • Willson T.A.
        • Stanley E.G.
        • et al.
        SOCS3 negatively regulates IL-6 signaling in vivo.
        Nat Immunol. 2003; 4: 540-545
        • Rehermann B.
        Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence.
        J Clin Invest. 2009; 119: 1745-1754
        • Ahlenstiel G.
        • Titerence R.H.
        • Koh C.
        • Edlich B.
        • Feld J.J.
        • Rotman Y.
        • et al.
        Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.
        Gastroenterology. 2010; 138 (e321–e322): 325-335
        • Cheent K.
        • Khakoo S.I.
        Natural killer cells and hepatitis C: action and reaction.
        Gut. 2011; 60: 268-278
        • Golden-Mason L.
        • Cox A.L.
        • Randall J.A.
        • Cheng L.
        • Rosen H.R.
        Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro.
        Hepatology. 2010; 52: 1581-1589
        • Amadei B.
        • Urbani S.
        • Cazaly A.
        • Fisicaro P.
        • Zerbini A.
        • Ahmed P.
        • et al.
        Activation of natural killer cells during acute infection with hepatitis C virus.
        Gastroenterology. 2010; 138: 1536-1545
        • Stegmann K.A.
        • Bjorkstrom N.K.
        • Veber H.
        • Ciesek S.
        • Riese P.
        • Wiegand J.
        • et al.
        Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.
        Gastroenterology. 2010; 138: 1885-1897
        • Ahlenstiel G.
        • Edlich B.
        • Hogdal L.J.
        • Rotman Y.
        • Noureddin M.
        • Feld J.J.
        • et al.
        Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C.
        Gastroenterology. 2011; 141 (e1232): 1231-1239
        • Wang S.H.
        • Huang C.X.
        • Ye L.
        • Wang X.
        • Song L.
        • Wang Y.J.
        • et al.
        Natural killer cells suppress full cycle HCV infection of human hepatocytes.
        J Viral Hepat. 2008; 15: 855-864
        • Miyagi T.
        • Takehara T.
        • Nishio K.
        • Shimizu S.
        • Kohga K.
        • Li W.
        • et al.
        Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection.
        J Hepatol. 2010; 53: 424-430
        • Edlich B.
        • Ahlenstiel G.
        • Azpiroz A.Z.
        • Stoltzfus J.
        • Noureddin M.
        • Serti E.
        • et al.
        Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C.
        Hepatology. 2012; 55: 39-48
        • Donnelly R.P.
        • Kotenko S.V.
        Interferon-lambda: a new addition to an old family.
        J Interferon Cytokine Res. 2010; 30: 555-564
        • Diegelmann J.
        • Beigel F.
        • Zitzmann K.
        • Kaul A.
        • Goke B.
        • Auernhammer C.J.
        • et al.
        Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.
        PLoS One. 2010; 5: e15200
        • Marcello T.
        • Grakoui A.
        • Barba-Spaeth G.
        • Machlin E.S.
        • Kotenko S.V.
        • MacDonald M.R.
        • et al.
        Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
        Gastroenterology. 2006; 131: 1887-1898
        • Donnelly R.P.
        • Dickensheets H.
        • O’Brien T.R.
        Interferon-lambda and therapy for chronic hepatitis C virus infection.
        Trends Immunol. 2011; 32: 443-450
        • Zhang L.
        • Jilg N.
        • Shao R.X.
        • Lin W.
        • Fusco D.N.
        • Zhao H.
        • et al.
        IL28B inhibits hepatitis C virus replication through the JAK–STAT pathway.
        J Hepatol. 2011; 55: 289-298
        • Pagliaccetti N.E.
        • Eduardo R.
        • Kleinstein S.H.
        • Mu X.J.
        • Bandi P.
        • Robek M.D.
        Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication.
        J Biol Chem. 2008; 283: 30079-30089
        • Robek M.D.
        • Boyd B.S.
        • Chisari F.V.
        Lambda interferon inhibits hepatitis B and C virus replication.
        J Virol. 2005; 79: 3851-3854
        • Muir A.J.
        • Shiffman M.L.
        • Zaman A.
        • Yoffe B.
        • de la Torre A.
        • Flamm S.
        • et al.
        Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.
        Hepatology. 2010; 52: 822-832
        • Ramos E.L.
        Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C.
        J Interferon Cytokine Res. 2010; 30: 591-595
        • Afdhal N.H.
        • McHutchison J.G.
        • Zeuzem S.
        • Mangia A.
        • Pawlotsky J.M.
        • Murray J.S.
        • et al.
        Hepatitis C pharmacogenetics: state of the art in 2010.
        Hepatology. 2011; 53: 336-345
        • Balagopal A.
        • Thomas D.L.
        • Thio C.L.
        IL28B and the control of hepatitis C virus infection.
        Gastroenterology. 2010; 139: 1865-1876
        • Lange C.M.
        • Zeuzem S.
        IL28B single nucleotide polymorphisms in the treatment of hepatitis C.
        J Hepatol. 2011; 55: 692-701
        • Lange C.M.
        • Moradpour D.
        • Doehring A.
        • Lehr H.A.
        • Mullhaupt B.
        • Bibert S.
        • et al.
        Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.
        J Hepatol. 2011; 55: 322-327
        • Fukuhara T.
        • Taketomi A.
        • Motomura T.
        • Okano S.
        • Ninomiya A.
        • Abe T.
        • et al.
        Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.
        Gastroenterology. 2010; 139: 1577-1585
        • Charlton M.R.
        • Thompson A.
        • Veldt B.J.
        • Watt K.
        • Tillmann H.
        • Poterucha J.J.
        • et al.
        Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection.
        Hepatology. 2011; 53: 317-324
        • Langhans B.
        • Kupfer B.
        • Braunschweiger I.
        • Arndt S.
        • Schulte W.
        • Nischalke H.D.
        • et al.
        Interferon-lambda serum levels in hepatitis C.
        J Hepatol. 2011; 54: 859-865
        • Abe H.
        • Hayes C.N.
        • Ochi H.
        • Maekawa T.
        • Tsuge M.
        • Miki D.
        • et al.
        IL28 variation affects expression of interferon stimulated genes and peg-interferon and ribavirin therapy.
        J Hepatol. 2011; 54: 1094-1101
        • Urban T.J.
        • Thompson A.J.
        • Bradrick S.S.
        • Fellay J.
        • Schuppan D.
        • Cronin K.D.
        • et al.
        IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.
        Hepatology. 2010; 52: 1888-1896
        • Makowska Z.
        • Duong F.H.
        • Trincucci G.
        • Tough D.F.
        • Heim M.H.
        Interferon-beta and interferon-lambda signaling is not affected by interferon-induced refractoriness to interferon-alpha in vivo.
        Hepatology. 2011; 53: 1154-1163
        • Radaeva S.
        • Jaruga B.
        • Hong F.
        • Kim W.H.
        • Fan S.
        • Cai H.
        • et al.
        Interferon-alpha activates multiple STAT signals and down-regulates c- Met in primary human hepatocytes.
        Gastroenterology. 2002; 122: 1020-1034
        • Mair M.
        • Blaas L.
        • Osterreicher C.H.
        • Casanova E.
        • Eferl R.
        JAK–STAT signaling in hepatic fibrosis.
        Front Biosci. 2011; 17: 2794-2811
        • Torisu T.
        • Nakaya M.
        • Watanabe S.
        • Hashimoto M.
        • Yoshida H.
        • Chinen T.
        • et al.
        Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis.
        Hepatology. 2008; 47: 1644-1654
        • Lafdil F.
        • Wang H.
        • Park O.
        • Zhang W.
        • Moritoki Y.
        • Yin S.
        • et al.
        Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production.
        Gastroenterology. 2009; 137 (e2121–e2122): 2125-2135
        • Klein C.
        • Wustefeld T.
        • Assmus U.
        • Roskams T.
        • Rose-John S.
        • Muller M.
        • et al.
        The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury.
        J Clin Invest. 2005; 115: 860-869
        • Siebler J.
        • Wirtz S.
        • Klein S.
        • Protschka M.
        • Blessing M.
        • Galle P.R.
        • et al.
        A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation.
        Hepatology. 2003; 38: 1573-1580
        • Zenewicz L.A.
        • Yancopoulos G.D.
        • Valenzuela D.M.
        • Murphy A.J.
        • Karow M.
        • Flavell R.A.
        Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
        Immunity. 2007; 27: 647-659
        • Ogata H.
        • Kobayashi T.
        • Chinen T.
        • Takaki H.
        • Sanada T.
        • Minoda Y.
        • et al.
        Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.
        Gastroenterology. 2006; 131: 179-193
        • Park O.
        • Wang H.
        • Weng H.
        • Feigenbaum L.
        • Li H.
        • Yin S.
        • et al.
        In vivo consequences of liver-specific interleukin-22 expression in mice. Implications for human liver disease progression.
        Hepatology. 2011; 54: 252-261
        • Siebler J.
        • Wirtz S.
        • Frenzel C.
        • Schuchmann M.
        • Lohse A.W.
        • Galle P.R.
        • et al.
        Cutting edge: a key pathogenic role of IL-27 in T cell-mediated hepatitis.
        J Immunol. 2008; 180: 30-33
        • Kim W.H.
        • Hong F.
        • Radaeva S.
        • Jaruga B.
        • Fan S.
        • Gao B.
        STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.
        Am J Physiol Gastrointest Liver Physiol. 2003; 285: G761-G768
        • Horiguchi N.
        • Lafdil F.
        • Miller A.M.
        • Park O.
        • Wang H.
        • Rajesh M.
        • et al.
        Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice.
        Hepatology. 2010; 51: 1724-1734
        • Mair M.
        • Zollner G.
        • Schneller D.
        • Musteanu M.
        • Fickert P.
        • Gumhold J.
        • et al.
        Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.
        Gastroenterology. 2010; 138: 2499-2508
        • Kroy D.C.
        • Beraza N.
        • Tschaharganeh D.F.
        • Sander L.E.
        • Erschfeld S.
        • Giebeler A.
        • et al.
        Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice.
        Hepatology. 2010; 51: 463-473
        • Horiguchi N.
        • Wang L.
        • Mukhopadhyay P.
        • Park O.
        • Jeong W.I.
        • Lafdil F.
        • et al.
        Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
        Gastroenterology. 2008; 134: 1148-1158
        • Ki S.H.
        • Park O.
        • Zheng M.
        • Morales-Ibanez O.
        • Kolls J.K.
        • Bataller R.
        • et al.
        Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.
        Hepatology. 2010; 52: 1291-1300
        • Haga S.
        • Terui K.
        • Zhang H.Q.
        • Enosawa S.
        • Ogawa W.
        • Inoue H.
        • et al.
        Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms.
        J Clin Invest. 2003; 112: 989-998
        • Taub R.
        Hepatoprotection via the IL-6/Stat3 pathway.
        J Clin Invest. 2003; 112: 978-980
        • Wang H.
        • Lafdil F.
        • Kong X.
        • Gao B.
        Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target.
        Int J Biol Sci. 2011; 7: 536-550
        • Sun R.
        • Park O.
        • Horiguchi N.
        • Kulkarni S.
        • Jeong W.I.
        • Sun H.Y.
        • et al.
        STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
        Hepatology. 2006; 44: 955-966
        • Jaruga B.
        • Hong F.
        • Kim W.H.
        • Gao B.
        IFN-{gamma}/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1.
        Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1044-G1052
        • Wang H.
        • Park O.
        • Lafdil F.
        • Shen K.
        • Horiguchi N.
        • Yin S.
        • et al.
        Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity.
        Hepatology. 2010; 51: 1354-1362
        • Li W.
        • Liang X.
        • Kellendonk C.
        • Poli V.
        • Taub R.
        STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration.
        J Biol Chem. 2002; 277: 28411-28417
        • Michalopoulos G.K.
        Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.
        Am J Pathol. 2010; 176: 2-13
        • Fausto N.
        • Campbell J.S.
        • Riehle K.J.
        Liver regeneration.
        Hepatology. 2006; 43: S45-S53
        • Cressman D.E.
        • Greenbaum L.E.
        • DeAngelis R.A.
        • Ciliberto G.
        • Furth E.E.
        • Poli V.
        • et al.
        Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.
        Science. 1996; 274 (New York, NY): 1379-1383
        • Sakamoto T.
        • Liu Z.
        • Murase N.
        • Ezure T.
        • Yokomuro S.
        • Poli V.
        • et al.
        Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy.
        Hepatology. 1999; 29: 403-411
        • Blindenbacher A.
        • Wang X.
        • Langer I.
        • Savino R.
        • Terracciano L.
        • Heim M.H.
        Interleukin 6 is important for survival after partial hepatectomy in mice.
        Hepatology. 2003; 38 (Baltimore, MD): 674-682
        • Sun R.
        • Jaruga B.
        • Kulkarni S.
        • Sun H.
        • Gao B.
        IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: regulation by SOCS3.
        Biochem Biophys Res Commun. 2005; 338: 1943-1949
        • Wuestefeld T.
        • Klein C.
        • Streetz K.L.
        • Betz U.
        • Lauber J.
        • Buer J.
        • et al.
        Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration.
        J Biol Chem. 2003; 278: 11281-11288
        • Dierssen U.
        • Beraza N.
        • Lutz H.H.
        • Liedtke C.
        • Ernst M.
        • Wasmuth H.E.
        • et al.
        Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration.
        J Biol Chem. 2008; 283: 9886-9895
        • Moh A.
        • Iwamoto Y.
        • Chai G.X.
        • Zhang S.S.
        • Kano A.
        • Yang D.D.
        • et al.
        Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery.
        Lab Invest. 2007; 87: 1018-1028
        • Riehle K.J.
        • Campbell J.S.
        • McMahan R.S.
        • Johnson M.M.
        • Beyer R.P.
        • Bammler T.K.
        • et al.
        Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3.
        J Exp Med. 2008; 205: 91-103
        • Sun R.
        • Gao B.
        Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma).
        Gastroenterology. 2004; 127: 1525-1539
        • Radaeva S.
        • Jaruga B.
        • Kim W.H.
        • Heller T.
        • Liang T.J.
        • Gao B.
        Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C.
        Biochem J. 2004; 379: 199-208
        • Sakamori R.
        • Takehara T.
        • Ohnishi C.
        • Tatsumi T.
        • Ohkawa K.
        • Takeda K.
        • et al.
        Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice.
        Hepatology. 2007; 46: 1564-1573
        • Wang H.
        • Lafdil F.
        • Wang L.
        • Park O.
        • Yin S.
        • Niu J.
        • et al.
        Hepatoprotective versus oncogenic functions of STAT3 in liver tumorigenesis.
        Am J Pathol. 2011; 179: 714-724
        • Murray P.J.
        Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response.
        Curr Opin Pharmacol. 2006; 6: 379-386
        • Numata K.
        • Kubo M.
        • Watanabe H.
        • Takagi K.
        • Mizuta H.
        • Okada S.
        • et al.
        Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity.
        J Immunol. 2007; 178: 3777-3785
        • Kaplan M.H.
        STAT4: a critical regulator of inflammation in vivo.
        Immunol Res. 2005; 31: 231-242
        • Rodriguez-Galan M.C.
        • Reynolds D.
        • Correa S.G.
        • Iribarren P.
        • Watanabe M.
        • Young H.A.
        Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity.
        J Immunol. 2009; 183: 740-748
        • Yoshida K.
        • Yang G.X.
        • Zhang W.
        • Tsuda M.
        • Tsuneyama K.
        • Moritoki Y.
        • et al.
        Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice.
        Hepatology. 2009; 50: 1494-1500
        • Zhu R.
        • Diem S.
        • Araujo L.M.
        • Aumeunier A.
        • Denizeau J.
        • Philadelphe E.
        • et al.
        The Pro-Th1 cytokine IL-12 enhances IL-4 production by invariant NKT cells: relevance for T cell-mediated hepatitis.
        J Immunol. 2007; 178: 5435-5442
        • Chang C.J.
        • Chen Y.H.
        • Huang K.W.
        • Cheng H.W.
        • Chan S.F.
        • Tai K.F.
        • et al.
        Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors.
        Hepatology. 2007; 45: 746-754
        • Harada N.
        • Shimada M.
        • Okano S.
        • Suehiro T.
        • Soejima Y.
        • Tomita Y.
        • et al.
        IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice.
        J Immunol. 2004; 173: 6635-6644
        • Subleski J.J.
        • Hall V.L.
        • Back T.C.
        • Ortaldo J.R.
        • Wiltrout R.H.
        Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver.
        Cancer Res. 2006; 66: 11005-11012
        • Shen X.D.
        • Ke B.
        • Zhai Y.
        • Gao F.
        • Anselmo D.
        • Lassman C.R.
        • et al.
        Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice. HO-1 dependence of Stat4 disruption-mediated cytoprotection.
        Hepatology. 2003; 37: 296-303
        • Kato A.
        • Graul-Layman A.
        • Edwards M.J.
        • Lentsch A.B.
        Promotion of hepatic ischemia/reperfusion injury by IL-12 is independent of STAT4.
        Transplantation. 2002; 73: 1142-1145
        • Jaruga B.
        • Hong F.
        • Sun R.
        • Radaeva S.
        • Gao B.
        Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
        J Immunol. 2003; 171: 3233-3244
        • Higuchi S.
        • Kobayashi M.
        • Yoshikawa Y.
        • Tsuneyama K.
        • Fukami T.
        • Nakajima M.
        • et al.
        IL-4 mediates dicloxacillin-induced liver injury in mice.
        Toxicol Lett. 2011; 200: 139-145
        • Njoku D.B.
        • Li Z.
        • Washington N.D.
        • Mellerson J.L.
        • Talor M.V.
        • Sharma R.
        • et al.
        Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury.
        Eur J Immunol. 2009; 39: 1652-1663
        • Douglas D.B.
        • Beiting D.P.
        • Loftus J.P.
        • Appleton J.A.
        • Bliss S.K.
        Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection.
        Hepatology. 2010; 51: 2162-2171
        • Ryan P.B.M.
        • Korrapati M.C.
        • Proctor W.R.
        • Vasquez R.V.
        • Yee S.B.
        • Quinn T.D.
        • et al.
        Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
        Chem Res Toxicol. 2012; 25: 83-93
        • Kato A.
        • Yoshidome H.
        • Edwards M.J.
        • Lentsch A.B.
        Reduced hepatic ischemia/reperfusion injury by IL-4: potential anti-inflammatory role of STAT6.
        Inflamm Res. 2000; 49: 275-279
        • Kato A.
        • Okaya T.
        • Lentsch A.B.
        Endogenous IL-13 protects hepatocytes and vascular endothelial cells during ischemia/reperfusion injury.
        Hepatology. 2003; 37: 304-312
        • Yoshidome H.
        • Kato A.
        • Miyazaki M.
        • Edwards M.J.
        • Lentsch A.B.
        IL-13 activates STAT6 and inhibits liver injury induced by ischemia/reperfusion.
        Am J Pathol. 1999; 155: 1059-1064
        • Ke B.
        • Shen X.D.
        • Gao F.
        • Busuttil R.W.
        • Kupiec-Weglinski J.W.
        Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection.
        Hum Gene Ther. 2004; 15: 691-698
        • Cao Z.
        • Yuan Y.
        • Jeyabalan G.
        • Du Q.
        • Tsung A.
        • Geller D.A.
        • et al.
        Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor.
        Am J Physiol Gastrointest Liver Physiol. 2009; 297: G249-G258
        • Adámková L.
        • Kovarík J.
        Transcription protein STAT1: biology and relation to cancer.
        Folia Biol (Praha). 2007; 53: 1-6
        • Kaplan D.H.
        • Shankaran V.
        • Dighe A.S.
        • Stockert E.
        • Aguet M.
        • Old L.J.
        • et al.
        Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.
        Proc Natl Acad Sci U S A. 1998; 95: 7556-7561
        • Lee C.K.
        • Smith E.
        • Gimeno R.
        • Gertner R.
        • Levy D.E.
        STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma.
        J Immunol. 2000; 164: 1286-1292
        • Zhu Z.Z.
        • Di J.Z.
        • Gu W.Y.
        • Cong W.M.
        • Gawron A.
        • Wang Y.
        • et al.
        Association of genetic polymorphisms in STAT1 gene with increased risk of hepatocellular carcinoma.
        Oncology. 2010; 78: 382-388
        • Nagano H.
        Treatment of advanced hepatocellular carcinoma: intraarterial infusion chemotherapy combined with interferon.
        Oncology. 2010; 78: 142-147
        • Haura E.B.
        • Turkson J.
        • Jove R.
        Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer.
        Nat Clin Pract Oncol. 2005; 2: 315-324
        • Yu H.
        • Jove R.
        The STATs of cancer – new molecular targets come of age.
        Nat Rev Cancer. 2004; 4: 97-105
        • He G.
        • Karin M.
        NF-kappaB and STAT3 – key players in liver inflammation and cancer.
        Cell Res. 2011; 21: 159-168
        • Lin L.
        • Amin R.
        • Gallicano G.I.
        • Glasgow E.
        • Jogunoori W.
        • Jessup J.M.
        • et al.
        The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling.
        Oncogene. 2009; 28: 961-972
        • Calvisi D.F.
        • Ladu S.
        • Gorden A.
        • Farina M.
        • Conner E.A.
        • Lee J.S.
        • et al.
        Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.
        Gastroenterology. 2006; 130: 1117-1128
        • Jiang R.T.Z.
        • Deng L.
        • Chen Y.
        • Xia Y.
        • Gao Y.
        • Wang X.
        • et al.
        Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.
        Hepatology. 2011; 54: 900-909
        • Yoshikawa H.
        • Matsubara K.
        • Qian G.S.
        • Jackson P.
        • Groopman J.D.
        • Manning J.E.
        • et al.
        SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.
        Nat Genet. 2001; 28: 29-35
        • Niwa Y.
        • Kanda H.
        • Shikauchi Y.
        • Saiura A.
        • Matsubara K.
        • Kitagawa T.
        • et al.
        Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.
        Oncogene. 2005; 24: 6406-6417
        • Zhang J.F.
        • He M.L.
        • Fu W.M.
        • Wang H.
        • Chen L.Z.
        • Zhu X.
        • et al.
        Primate-specific miRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting stat3 signaling.
        Hepatology. 2011; 54: 2137-2148
        • Avella D.M.
        • Li G.
        • Schell T.D.
        • Liu D.
        • Shao-Min Zhang S.
        • et al.
        Regression of established hepatocellular carcinoma is induced by chemo-immunotherapy in an orthotopic murine model.
        Hepatology. 2012; 55: 141-152
        • Wang C.
        • Yang W.
        • Yan H.X.
        • Luo T.
        • Zhang J.
        • Tang L.
        • et al.
        HBx induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treated HBx transgenic mice.
        Hepatology. 2012; 55: 108-120
        • Naugler W.E.
        • Sakurai T.
        • Kim S.
        • Maeda S.
        • Kim K.
        • Elsharkawy A.M.
        • et al.
        Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
        Science. 2007; 317: 121-124
        • Park E.J.
        • Lee J.H.
        • Yu G.Y.
        • He G.
        • Ali S.R.
        • Holzer R.G.
        • et al.
        Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
        Cell. 2010; 140: 197-208
        • Bard-Chapeau E.A.
        • Li S.
        • Ding J.
        • Zhang S.S.
        • Zhu H.H.
        • Princen F.
        • et al.
        Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis.
        Cancer Cell. 2011; 19: 629-639
        • He G.
        • Yu G.Y.
        • Temkin V.
        • Ogata H.
        • Kuntzen C.
        • Sakurai T.
        • et al.
        Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
        Cancer Cell. 2010; 17: 286-297
        • Schneller D.
        • Machat G.
        • Sousek A.
        • Proell V.
        • van Zijl F.
        • Zulehner G.
        • et al.
        P19(ARF)/p14(ARF) controls oncogenic functions of signal transducer and activator of transcription 3 in hepatocellular carcinoma.
        Hepatology. 2011; 54: 164-172
        • Calvisi D.F.
        Dr. Jekyll, Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer.
        Hepatology. 2011; 54: 9-12
        • Ferbeyre G.
        • Moriggl R.
        The role of Stat5 transcription factors as tumor suppressors or oncogenes.
        Biochim Biophys Acta. 2011; 1815: 104-114
        • Hosui A.
        • Kimura A.
        • Yamaji D.
        • Zhu B.M.
        • Na R.
        • Hennighausen L.
        Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation.
        J Exp Med. 2009; 206: 819-831
        • Mueller K.M.
        • Kornfeld J.W.
        • Friedbichler K.
        • Blaas L.
        • Egger G.
        • Esterbauer H.
        • et al.
        Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
        Hepatology. 2011; 54: 1398-1409
        • Friedbichler K.T.M.
        • Mueller K.M.
        • Schlederer M.
        • Kornfeld J.W.
        • Terracciano L.M.
        • Kozlov A.V.
        • et al.
        Growth hormone-induced STAT5 signaling causes gigantism, inflammation and premature death but protects mice from aggressive liver cancer.
        Hepatology. 2012; 55: 941-952
        • Yu J.H.
        • Zhu B.M.
        • Wickre M.
        • Riedlinger G.
        • Chen W.
        • Hosui A.
        • et al.
        The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B negatively regulate cell proliferation through the activation of cyclin-dependent kinase inhibitor 2b (Cdkn2b) and Cdkn1a expression.
        Hepatology. 2010; 52: 1808-1818
        • Feld J.J.
        • Modi A.A.
        • El-Diwany R.
        • Rotman Y.
        • Thomas E.
        • Ahlenstiel G.
        • et al.
        S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders.
        Gastroenterology. 2011; 140: 830-839
        • Page B.D.
        • Ball D.P.
        • Gunning P.T.
        Signal transducer and activator of transcription 3 inhibitors: a patent review.
        Expert Opin Ther Pat. 2011; 21: 65-83
        • Iavarone M.
        • Cabibbo G.
        • Piscaglia F.
        • Zavaglia C.
        • Grieco A.
        • Villa E.
        • et al.
        Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
        Hepatology. 2011; 54: 2055-2063
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • Villanueva A.
        • Llovet J.M.
        Targeted therapies for hepatocellular carcinoma.
        Gastroenterology. 2011; 140: 1410-1426
        • Siegel A.B.
        • Olsen S.K.
        • Magun A.
        • Brown Jr., R.S.
        Sorafenib: where do we go from here?.
        Hepatology. 2010; 52: 360-369
        • Blechacz B.R.
        • Smoot R.L.
        • Bronk S.F.
        • Werneburg N.W.
        • Sirica A.E.
        • Gores G.J.
        Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2.
        Hepatology. 2009; 50: 1861-1870
        • Tai W.T.
        • Cheng A.L.
        • Shiau C.W.
        • Huang H.P.
        • Huang J.W.
        • Chen P.J.
        • et al.
        Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma.
        J Hepatol. 2011; 55: 1041-1048
        • Rosmorduc O.
        • Desbois-Mouthon C.
        Targeting STAT3 in hepatocellular carcinoma: Sorafenib again.
        J Hepatol. 2011; 55: 957-959