- •Liver injury in patients with COVID-19 is associated with elevated IL-6 and coagulopathy.
- •Patients with COVID-19 exhibit hepatic endotheliopathy which is associated with liver injury.
- •IL-6 trans-signaling causes endotheliopathy in liver sinusoidal endothelial cells.
Background and Aims
- Nishimoto N.
- Terao K.
- Mima T.
- Nakahara H.
- Takagi N.
- Kakehi T.
Materials and methods
COVID-19 patient data
Patients for clinicopathological study
Supplementary materials and methods
Liver injury is associated with coagulopathy and elevated IL-6 in patients with COVID-19
Endotheliopathy in the liver is associated with liver inflammation and injury in COVID-19
IL-6 trans-signaling in LSECs mediates endotheliopathy, cell surface expression of vWF, and platelet attachment
- Nishimoto N.
- Terao K.
- Mima T.
- Nakahara H.
- Takagi N.
- Kakehi T.
Soluble gp130 (sgp130) blocks JAK1 and STAT3 phosphorylation induced by IL-6 trans-signaling in LSECs
JAK inhibitor ruxolitinib efficiently blocks JAK/STAT induction by IL-6 trans-signaling and procoagulant endotheliopathy in LSECs
LSEC-hepatocyte crosstalk amplifies hyperfibrinogenemia in COVID-19
Data availability statement
Conflict of interest
- Multimedia component 1
- Multimedia component 2
- Multimedia component 3
- COVID-19 as the leading cause of death in the United States.JAMA. 2021; 325: 123-124
- Liver disease and COVID-19: from pathogenesis to clinical care.Hepatology. 2020;
- Acute liver injury in COVID-19: prevalence and association with clinical outcomes in a large U.S. Cohort.Hepatology. 2020; 72: 807-817
- Abnormal liver tests in COVID-19: a retrospective observational cohort study of 1,827 patients in a major U.S. Hospital network.Hepatology. 2020; 72: 1169-1176
- Correlation between liver function tests abnormalities and interleukin-6 serum levels in patients with SARS-CoV-2 infection.Gastroenterology. 2020;
- Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations.Liver Int. 2020; 40: 2110-2116
- Association of coagulopathy with liver dysfunction in patients with COVID-19.Hepatol Res. 2020;
- Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847
- Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis.J Thromb Haemost. 2020; 18: 1738-1742
- Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.Lancet Haematol. 2020; 7: e575-e582
- Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII.J Thromb Haemost. 2014; 12: 36-42
- Elevated interleukin-6 is associated with severity of COVID-19: a meta-analysis.J Med Virol. 2020;
- Elevated interleukin-6 and severe COVID-19: a meta-analysis.J Med Virol. 2020; 92: 2283-2285
- Systemic inflammation as fuel for acute liver injury in COVID-19.Dig Liver Dis. 2021; 53: 158-165
- Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts.J Biol Chem. 2002; 277: 16879-16887
- Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6.receptor complex.J Biol Chem. 1996; 271: 20138-20144
- SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc.Cytokine X. 2020; 2: 100029
- Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells.Cell Commun Signal. 2018; 16: 55
- Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation.Am J Physiol Cell Physiol. 2009; 297: C1294-C1306
- IL-6 pathway in the liver: from physiopathology to therapy.J Hepatol. 2016; 64: 1403-1415
- IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.Proc Natl Acad Sci U S A. 2020; 117: 22351-22356
- Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease.Blood. 2008; 112: 3959-3964
- SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells.Plos Pathog. 2020; 16e1009128
- ACG clinical guideline: evaluation of abnormal liver chemistries.Am J Gastroenterol. 2017; 112: 18-35
- Linking inflammation and thrombosis: role of C-reactive protein.World J Cardiol. 2010; 2: 365-369
- Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.Nat Rev Cardiol. 2020;
- Accumulation of platelets in the liver may be an important contributory factor to thrombocytopenia and liver fibrosis in chronic hepatitis C.J Gastroenterol. 2013; 48: 526-534
- Soluble interleukin-6 receptor is elevated during influenza A virus infection and mediates the IL-6 and IL-32 inflammatory cytokine burst.Cell Mol Immunol. 2015; 12: 633-644
- The soluble interleukin 6 receptor: mechanisms of production and implications in disease.FASEB J. 2001; 15: 43-58
- Expression of factor VIII by murine liver sinusoidal endothelial cells.J Biol Chem. 1999; 274: 19587-19592
- Adhesion mechanisms in platelet function.Circ Res. 2007; 100: 1673-1685
- Fibrinogen promotes neutrophil activation and delays apoptosis.J Immunol. 2001; 166: 2002-2010
- Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.Hepatology. 2006; 44: 53-61
- Postmortem findings in Italian patients with COVID-19: a descriptive full autopsy study of cases with and without comorbidities.J Infect Dis. 2020; 222: 1807-1815
- Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series.EClinicalMedicine. 2020; 24: 100434
- Soluble fibrinogen modulates neutrophil functionality through the activation of an extracellular signal-regulated kinase-dependent pathway.J Immunol. 2002; 168: 3527-3535
- Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19.N Engl J Med. 2020; 383: 120-128
- IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.Hepatology. 2017; 65: 89-103
- Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells.Am J Physiol Cell Physiol. 2021;
- Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial.J Allergy Clin Immunol. 2020; 146: 137-146 e133
- Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study.Leukemia. 2020;
- Tocilizumab in patients hospitalized with covid-19 pneumonia.N Engl J Med. 2021; 384: 20-30
Author names in bold designate co-first authorship