|
1
|
Yang Y, Tu ZK, Liu XK, Zhang P. Mononuclear phagocyte system in hepatitis C virus infection. World J Gastroenterol 2018; 24:4962-4973. [PMID: 30510371 PMCID: PMC6262249 DOI: 10.3748/wjg.v24.i44.4962] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/30/2018] [Accepted: 11/08/2018] [Indexed: 02/06/2023] Open
Abstract
The mononuclear phagocyte system (MPS), which consists of monocytes, dendritic cells (DCs), and macrophages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus (HCV) is efficient in evading the host immunity, thereby facilitating its development into chronic infection. Chronic HCV infection is the leading cause of end-stage liver diseases, liver cirrhosis, and hepatocellular carcinoma. Acquired immune response was regarded as the key factor to eradicate HCV. However, innate immunity can regulate the acquired immune response. Innate immunity-derived cytokines shape the adaptive immunity by regulating T-cell differentiation, which determines the outcome of acute HCV infection. Inhibition of HCV-specific T-cell responses is one of the most important strategies for immune system evasion. It is meaningful to illustrate the role of innate immune response in HCV infection. With the MPS being the important factor in innate immunity, therefore, understanding the role of the MPS in HCV infection will shed light on the pathophysiology of chronic HCV infection. In this review, we outline the impact of HCV infection on the MPS and cytokine production. We discuss how HCV is detected by the MPS and describe the function and impairment of MPS components in HCV infection.
Collapse
Affiliation(s)
- Yu Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng-Kun Tu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Xing-Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| |
Collapse
|
|
2
|
Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
Collapse
Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| |
Collapse
|
|
3
|
Flynn JK, Dore GJ, Hellard M, Yeung B, Rawlinson WD, White PA, Kaldor JM, Lloyd AR, Ffrench RA. Early IL-10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users. J Viral Hepat 2011; 18:549-61. [PMID: 20626625 PMCID: PMC4277610 DOI: 10.1111/j.1365-2893.2010.01335.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin-10 (IL-10) production (P = 0.048), in the relative absence of interferon-gamma (IFN-γ) and IL-2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN-γ (magnitude P < 0.001, breadth P = 0.004) and IL-2 responses, in the relative absence of IL-10. Early IL-10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN-γ and IL-2 production was inversely correlated with HCV RNA level at baseline (IFN-γ P = 0.020, IL-2 P = 0.050) and week 48 (IFN-γ P = 0.045, IL-2 P = 0.026). Intracellular staining (ICS) indicated the HCV-specific IFN-γ response was primarily from CD8(+) T cells and NK cells, whereas IL-10 production was predominantly from monocytes, with a subset of IL-10 producing CD8(+) T cells present only in those who progressed to chronic infection. IL-10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.
Collapse
Affiliation(s)
| | - Gregory J Dore
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | - Barbara Yeung
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - William D Rawlinson
- Virology Division, Southern Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia
| | - Peter A White
- School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia
| | - John M Kaldor
- National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | | | | |
Collapse
|
|
4
|
Liu BS, Groothuismink ZMA, Janssen HLA, Boonstra A. Role for IL-10 in inducing functional impairment of monocytes upon TLR4 ligation in patients with chronic HCV infections. J Leukoc Biol 2011; 89:981-8. [PMID: 21385948 DOI: 10.1189/jlb.1210680] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The consequences of chronic infection with the HCV on immunity to distinct pathogens are not fully appreciated, despite the potent modulatory effects of HCV on the immune system. We observed that upon TLR4 ligation, monocytes from chronic HCV patients demonstrated three to five times lower TNF and IL-12p40 production as compared with healthy individuals. However, augmented production of TNF, IL-12p40, and IL-12p70 by monocytes was observed upon stimulation with R848. Importantly, we observed that the levels of IL-10 in chronic HCV patients are higher in serum and that more IL-10 is produced by monocytes as compared with healthy individuals. The inhibitory effect of IL-10 on the production of proinflammatory cytokines by monocytes was only observed upon LPS stimulation but not upon R848 stimulation, showing that only the TLR4 pathway in monocytes is sensitive to the suppressive effects of IL-10. Interestingly, monocytes stimulated with the TLR4 agonist, but not TLR8 agonist, produced higher levels of IL-10 when exposed to patient serum as compared with serum from healthy individuals. Our results indicate that by differentially affecting TLR4 and TLR8 pathways, IL-10 may mediate highly selective modulation of the function of monocytes observed in chronic HCV patients. This suggests that there is no overall increased susceptibility to pathogens but a specific suppression of the functionality of TLR4 signaling pathway in monocytes, which is, at least partly, mediated via IL-10.
Collapse
Affiliation(s)
- Bi-Sheng Liu
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | | | | | | |
Collapse
|
|
5
|
Kaplan DE, Ikeda F, Li Y, Nakamoto N, Ganesan S, Valiga ME, Nunes FA, Rajender Reddy K, Chang KM. Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis. J Hepatol 2008; 48:903-13. [PMID: 18384906 PMCID: PMC2430081 DOI: 10.1016/j.jhep.2008.01.030] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 01/11/2008] [Accepted: 01/18/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Interleukin-10 (IL-10) has been ascribed pro-viral but anti-fibrotic properties in chronic hepatitis C virus (HCV) infection. In this study, we examined the role of HCV-specific T-cell IL-10 response in patients with acute and chronic HCV infection. METHODS Peripheral HCV-specific T-cell IL-10 and IFNgamma responses were measured in cytokine Elispot assay using overlapping HCV-derived peptides in patients with chronic (n=61), resolved (n=15) and acute (n=8) hepatitis C, looking for their onset, quantity, breadth and durability relative to clinical and virological outcomes. The source and effect of HCV-specific IL-10 response were determined in depletion and IL-10 neutralization experiments. RESULTS Both HCV-specific IL-10 and IFNgamma responses were detected early within 1-2 months of acute clinical hepatitis C. However, only HCV-specific IL-10 response correlated with elevated liver enzymes, increased viremia and suppressed HCV-specific CD4(+) T-cell proliferation in acute infection. While these associations were lost in established chronic infection, HCV-specific IL-10 responses were increased in patients without cirrhosis while IL-10 blockade enhanced antiviral effector IFNgamma responses. CONCLUSIONS HCV-specific IL-10 Tr1 responses may play a dual role in HCV infection, dampening effector T-cells to promote viral persistence in acute infection but also protecting against progressive fibrosis in chronic infection.
Collapse
Affiliation(s)
- David E Kaplan
- Research Section, Philadelphia VA Medical Center, Research A216, 3900 Woodland Avenue, Philadelphia, PA 19104, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Dambacher J, Beigel F, Zitzmann K, Heeg MHJ, Göke B, Diepolder HM, Auernhammer CJ, Brand S. The role of interleukin-22 in hepatitis C virus infection. Cytokine 2008; 41:209-16. [PMID: 18191408 DOI: 10.1016/j.cyto.2007.11.016] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 11/01/2007] [Accepted: 11/17/2007] [Indexed: 12/25/2022]
Abstract
In this study, we analyzed if IL-22 displays, similar to other IL-10 like cytokines such as IL-28A, antiviral properties in hepatic cells. Using RT-PCR and immunoblotting, we demonstrated that hepatic cell lines and primary hepatocytes express the functional IL-22 receptor complex consisting of IL-22R1 and IL-10R2. Hepatic IL-22 mRNA expression as measured by quantitative PCR was up-regulated in autoimmune and viral hepatitis compared to cholestatic liver diseases, while IL-22 serum levels did not differ significantly between patients with viral hepatitis and normal controls. IL-22 did not significantly change the expression levels of IFN-alpha/-beta and of the antiviral proteins MxA and 2',5'-OAS. Consequently, it had in comparison to IFN-alpha no relevant antiviral activity in in vitro models of HCV replication and infection. Taken together, hepatic IL-22 expression is up-regulated in viral hepatitis but IL-22 does not directly regulate antiviral proteins and has, in contrast to IFN-alpha, no effect on HCV replication.
Collapse
Affiliation(s)
- Julia Dambacher
- Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Marchioninistr. 15, 81377 Munich, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Fainboim L, Cherñavsky A, Paladino N, Flores AC, Arruvito L. Cytokines and chronic liver disease. Cytokine Growth Factor Rev 2007; 18:143-57. [PMID: 17324606 DOI: 10.1016/j.cytogfr.2007.01.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
From an immunological point of view, the healthy liver has been usually associated with the phenomenon of tolerance. A microenvironment of regulatory cytokines produced by liver Kuppfer cells and liver sinusoidal endothelial cells has contributed, together with resident dendritic cells, to generate a tolerogenic environment in this tissue. In this review we discussed the intrahepatic responses to different sorts of liver injury, such as hepatotrophic viruses, alcohol or putative self-antigens. In each case we analyzed the impact of different cytokines in the clinical outcome of the different pathological situations.
Collapse
Affiliation(s)
- Leonardo Fainboim
- Hospital de Clínicas José de San Martín, and Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
| | | | | | | | | |
Collapse
|
|
8
|
Byrnes AA, Li DY, Park K, Thompson D, Mocilnikar C, Mohan P, Molleston JP, Narkewicz M, Zhou H, Wolf SF, Schwarz KB, Karp CL. Modulation of the IL-12/IFN-γ axis by IFN-α therapy for hepatitis C. J Leukoc Biol 2006; 81:825-34. [PMID: 17148690 DOI: 10.1189/jlb.1006622] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
Collapse
Affiliation(s)
- Adriana A Byrnes
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Ciccaglione AR, Stellacci E, Marcantonio C, Muto V, Equestre M, Marsili G, Rapicetta M, Battistini A. Repression of interferon regulatory factor 1 by hepatitis C virus core protein results in inhibition of antiviral and immunomodulatory genes. J Virol 2006; 81:202-14. [PMID: 17050603 PMCID: PMC1797261 DOI: 10.1128/jvi.01011-06] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferon-stimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.
Collapse
Affiliation(s)
- Anna R Ciccaglione
- Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299 Rome 00161, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Conte E, Modica A, Cacopardo B, Messina L, Nigro L, Messina A. Ribavirin up-regulates IL-12 p40 gene expression and restores IL-12 levels in Leishmania-treated PBMCs. Parasite Immunol 2005; 27:447-51. [PMID: 16255743 DOI: 10.1111/j.1365-3024.2005.00796.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ribavirin, a nucleoside analogue that interferes with viral mRNA synthesis and inhibits the replication of RNA and DNA viruses, has been recently proposed as an effective immune response modulator. In the present report, we studied the effect of ribavirin on IL-12 p40 gene expression in peripheral blood mononuclear cells (PBMCs) of healthy subjects. We also studied ribavirin effects on PBMCs activated with lipopolysaccharide (LPS) and phytohaemagglutinin (PHA) and treated with Leishmania donovani antigens. We provide evidence that ribavirin was able to up-regulate IL-12 p40 gene expression and to restore levels of IL-12 p40 gene expression and IL-12 secretion in fully activated PBMCs that were strongly inhibited by L. donovani antigens. Because effective management of leishmanial disease is usually associated with a prevalent T-helper 1 immune response with elevated production of IL-12,our preliminary results may be of particular interest, provided that they will be confirmed by further in vitro and in vivo studies, when considering a possible use of ribavirin as adjuvant in severe leishmanial disease.
Collapse
Affiliation(s)
- E Conte
- Department of Biomedical Sciences, Section of General Pathology, University of Catania, Italy.
| | | | | | | | | | | |
Collapse
|
|
11
|
Panasiuk A, Prokopowicz D, Panasiuk B. Monocyte chemotactic protein-1 and soluble adhesion molecules as possible prognostic markers of the efficacy of antiviral treatment in chronic hepatitis C. World J Gastroenterol 2004; 10:3639-42. [PMID: 15534921 PMCID: PMC4612007 DOI: 10.3748/wjg.v10.i24.3639] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explain the role of Monocyte chemotactic protein-1 (MCP-1) and soluble adhesion molecules in chronic hepatitis C during the treatment of interferon alpha (IFNα ) 2 b and ribavirin (RBV).
METHODS: Concentrations of MCP-1, soluble adhesion molecules intercellular adhesion molecule-1 (sICAM-1), sP-selectin, interleukin (IL) 6, and IL10 in serum were estimated in the group of 40 patients with chronic hepatitis C treated with IFNalpha2 b and RBV in 0, 16, 32, 48 wk of the therapy.
RESULTS: In chronic hepatitis C, before and during the treatment, the serum levels of MCP-1 and sP-selectin in responders were similar to those of healthy subjects. In non-responders (NR), MCP-1 increased in the course of IFNα + RBV treatment, differences were statistically significant as compared to responders. MCP-1 correlated statistically with the activity of periportal inflammation (r = 0.35, P < 0.05) but not with staging of liver fibrosis. sICAM-1 positively correlated with inflammatory activity and fibrosis in NR. sP-selectin did not correlate with histological findings in the liver. The MCP-1 correlated with the soluble form of sP-selectin concentrations (r = 6, P < 0.001) and with IL-10 level in NR (r = 0.4, P < 0.05). There was no correlation observed between the concentration of MCP-1 and sICAM-1, IL-6 during the treatment.
CONCLUSION: MCP-1 concentration may be a prognostic marker of the efficacy of IFN + RBV therapy in patients with chronic hepatitis C.
Collapse
Affiliation(s)
- Anatol Panasiuk
- Department of Infectious Diseases, Medical University of Bialystok, 15-540 Bialystok, Zurawia Str., 14, Poland.
| | | | | |
Collapse
|
|
12
|
Mueller T, Mas-Marques A, Sarrazin C, Wiese M, Halangk J, Witt H, Ahlenstiel G, Spengler U, Goebel U, Wiedenmann B, Schreier E, Berg T. Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection. J Hepatol 2004; 41:652-8. [PMID: 15464247 DOI: 10.1016/j.jhep.2004.06.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2004] [Revised: 06/20/2004] [Accepted: 06/25/2004] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.
Collapse
Affiliation(s)
- Tobias Mueller
- Charité, Campus Virchow-Klinikum, Medizinische Klinik mit Schwerpunkt, Hepatologie und Gastroenterologie, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Eisen-Vandervelde AL, Waggoner SN, Yao ZQ, Cale EM, Hahn CS, Hahn YS. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem 2004; 279:43479-86. [PMID: 15292184 DOI: 10.1074/jbc.m407640200] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon-gamma production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon-gamma synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1beta, and tumor necrosis factor alpha. In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening TH1 responses.
Collapse
|
|
14
|
Schvoerer E, Navas MC, Thumann C, Fuchs A, Meyer N, Habersetzer F, Stoll-Keller F. Production of interleukin-18 and interleukin-12 in patients suffering from chronic hepatitis C virus infection before antiviral therapy. J Med Virol 2003; 70:588-93. [PMID: 12794721 DOI: 10.1002/jmv.10434] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interleukin-12 and -18 (IL-12 and IL-18) are known to enhance the cytotoxic T-lymphocyte response synergistically, but their precise involvement in hepatitis C virus (HCV) infection is not well known, especially for IL-18. Enzyme-linked immunosorbent assay (ELISA) was used to study the production of these cytokines in plasma and peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) of patients infected chronically with HCV before initiation of antiviral therapy. Fifty-six patients and 40 healthy controls were evaluated. Patients infected with genotype 1 or with genotype other than genotype 1 HCV had significantly a high production of plasma IL-12 compared with controls (P < 0.05). However, patients infected with genotype 1 HCV had lower levels of PBMC IL-18 than were founded in the controls (P < 0.05); plasma IL-18 also tended to be lower in this group of patients than in the controls, although nonsignificantly. Plasma IL-18 was related to hepatic histological activity (P < 0.05). The data suggest a relationship between these two cytokines and some features of HCV infection, so that their respective production in relation to the outcome of the infection deserves further study.
Collapse
Affiliation(s)
- E Schvoerer
- Institut de Virologie et Unité INSERM 544, Université Louis Pasteur, Strasbourg, France.
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Dolganiuc A, Kodys K, Kopasz A, Marshall C, Do T, Romics L, Mandrekar P, Zapp M, Szabo G. Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 170:5615-24. [PMID: 12759441 DOI: 10.4049/jimmunol.170.11.5615] [Citation(s) in RCA: 191] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-alpha production in monocytes. Degradation of I-kappa B alpha suggested involvement of NF-kappa B activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-alpha and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients' DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.
Collapse
Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | | | | | | | | | | | | | | | | |
Collapse
|