Abstract
Background/Aims: Tumor necrosis factor-alpha (TNF) is a mediator of inflammation and cellular immune
response. Soluble TNF receptors (sTNFR) sTNF-R55 and sTNF-R75, which compete with
cellular receptors for the binding of TNF, have been detected at high levels in infectious
diseases including human immunodeficiency virus and HBV infection. In order to investigate
the activation of the TNF system in HCV infection, we have analyzed the balance between
TNF and sTNF-R in 60 HCV-infected subjects according to their clinical, biological,
virological and histological characteristics.
Methods: Serum TNF, sTNF-R55 and sTNF-R75 levels were determined by ELISA before any therapy
and were compared to a control group of 60 healthy subjects and a group of 34 HBV-infected
patients.
Results: Mean TNF levels were 50.5±4.5 pg/ml in HCV patients, and undetectable (<5 pg/ml)
in the control subjects. sTNF-R55 and sTNF-R75 levels were significantly higher in
HCV-infected patients than in the controls: 2.88±0.14 ng/ml vs 1.30±0.05, (p=0.0001), and 9.54±0.58 ng/ml vs 4.19±016, (p=0.0001), respectively. sTNF-R55 and TNF-α levels inHCV patients were not significantly
different from levels in HBV patients. sTNF-R75 levels were slightly lower than in
HBV patients (9.54±0.58 vs 11.4±0.79 ng/ml, p=0.03). In contrast to other infectious diseases, there was no correlation between
levels of sTNF-R and TNE. sTNF-R75 but not TNF levels were correlated with aminotransferases
levels (p=0.0001 and p=0.0015 for aspartate and alanine aminotransferase, respectively), while sTNF-R55
levels were significantly correlated only with aspartate aminotransferase levels (p=0.003). sTNF-R75 levels were significantly correlated with the Metavir activity index
(p=0.01), and sTNF-R55 and sTNF-R75 levels were significantly higher in patients with
vs. without cirrhosis (3.22±0.21 vs. 2.54±0.17 ng/ml (p<0.02) and 11.6±0.86 vs. 7.5±0.53 ng/ml (p<0.001), respectively). sTNF-R55, sTNF-R75 and TNF levels were not correlated with
viral load, genotype or response to interferon therapy.
Conclusions: Levels of soluble TNF receptors, and particularly sTNF-R75, are significantly correlated
with the severity of the disease but not with virological parameters such as quantitative
viremia and genotype. High TNF-R production could thus suggest that HCV-related liver
disease involves immunological mechanisms, including activation of the TNF system.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cachectin (tumor necrosis factor): a macrophage hormone governing cellular metabolism and inflammatory response.Endocr Rev. 1988; 9: 57-66
- Cachectin/tumour necrosis factor.Lancet. 1989; i: 1122-1125
- Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies.Proc Natl Acad Sci USA. 1990; 87: 3127-3131
- Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha).J Biol Chem. 1989; 264: 14927-14934
- Two tumor necrosis factorbinding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors.J Biol Chem. 1990; 265: 1531-1536
- Isolation and characterization of a tumor necrosis factor binding protein from urine.Eur J Haematol. 1989; 42: 270-275
- Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor.J Biol Chem. 1989; 264: 11966-11973
- p55 and p75 tumor necrosis factor receptors in patients with chronic lymphocytic leukemia.Blood. 1992; 80: 2577-2583
- Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus.Arthritis Rheum. 1993; 36: 1111-1120
- Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases.Arthritis Rheum. 1992; 35: 1160-1169
- Differential expression of proinflammatory cytokines and their inhibitors during the course of meningococcal infections.J Infect Dis. 1994; 169: 157-161
- Monocyte tumor necrosis factor receptor levels as a predictor of risk in human sepsis.Arch Surg. 1996; 131: 434-437
- Soluble receptors for tumour necrosis factor: a putative marker of disease progression in HIV infection.AIDS. 1993; 7: 33-36
- Soluble tumor necrosis factor-alpha receptor type II (sTNF alpha RII) correlates with human immunodeficiency virus (HIV) RNA copy number in HIV-infected patients.J Infect Dis. 1996; 173: 464-467
- Soluble tumour necrosis factor receptors (sTNF-R) and HIV infection: correlation to CD8+ lymphocytes.Clin Exp Immunol. 1993; 93: 350-355
- Serum level of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection: correlations to clinical, immunologic, and virologic parameters.J Infect Dis. 1994; 169: 420-424
- Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection.Gastroenterology. 1995; 108: 1453-1463
- Pathobiologic effects of hepatitis C.J Hepatol. 1995; 22: 83-86
- Tumor necrosis factor alpha production by peripheral blood mononuclear cells of patients with chronic liver disease.Hepatology. 1989; 10: 769-773
- Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo.Proc Natl Acad Sci USA. 1992; 89: 4845-4849
- Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino acid sequence data of its soluble form, encodes both the cell surface and a soluble form of the receptor.EMBO J. 1990; 9: 3269-3278
- Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils.J Biol Chem. 1994; 269: 2834-2840
- Human neutrophil elastase releases a ligand-binding fragment from the 75-kDa tumor necrosis factor (TNF) receptor.J Biol Chem. 1991; 266: 18846-18853
- Polymorphonuclear granulocytes enhance lipopolysaccharide-induced soluble p75 tumor necrosis factor receptor release from mononuclear cells.Eur J Immunol. 1995; 25: 2714-2717
- Induction of soluble tumor necrosis factor receptor (sTNF-R75) release by HIV adsorption on cultured human monocytes.Eur J Immunol. 1994; 24: 2055-2060
- Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes.Eur J Immunol. 1994; 24: 2699-2705
- Induction of soluble tumour necrosis factor receptors during treatment with interleukin-2.Br J Cancer. 1992; 66: 1195-1199
- Infusion of tumor necrosis factor (TNF) causes an increase in circulating TNF-binding protein in humans.Cytokine. 1990; 2: 402-406
- TNF induces internalization of the p60 receptor and shedding of the p80 receptor.J Immunol. 1994; 152: 3550-3558
- Inflammatory cytokines and inhibitors in HIV infection: correlation between interleukin-1 receptor antagonist and weight loss.AIDS. 1996; 10: 1349-1356
- Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Rclationships with activation markers of T cells, B cells, and monocytes.J Immunol. 1995; 154: 882-892
- Hepatic expression of type A and type B receptors for tumor necrosis factor.J Hepatol. 1992; 14: 361-369
- Evidence for different effects of soluble TNF-receptors on various TNF measurements in human biological fluids.Lancet. 1991; 338: 515-516
- Tumor necrosis factor alpha expression and the response to interferon in chronic hepatitis C.Hepatology. 1996; 23: 210-217
- Characteristics of hepatitis C virus type II (1b) infection in France and Italy.Ann Intern Med. 1995; 122: 160-168
- Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans.Blood. 1995; 85: 433-435
Article info
Publication history
Accepted:
September 8,
1998
Received in revised form:
August 17,
1998
Received:
February 23,
1998
Identification
Copyright
© 1999 Published by Elsevier Inc.
