Hepatitis C Virus Core Protein Induces Homotolerance and Cross-Tolerance to Toll-Like Receptor Ligands by Activation of Toll-Like Receptor 2

• Published in: The Journal of infectious diseases Vol. 202; no. 6; pp. 853 - 861
• Main Authors: Chung, Hobyung, Watanabe, Tomohiro, Kudo, Masatoshi, Chiba, Tsutomu
• Format: Journal Article
• Language: English
• Published: Oxford University Chicago Press 15.09.2010; University of Chicago Press; Oxford University Press
• Subjects: Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - virology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Cytokines; Fundamental and applied biological sciences. Psychology; Hepacivirus; Hepacivirus - immunology; Hepacivirus - pathogenicity; Hepatitis C, Chronic - immunology; Humans; Immune Tolerance; Infections; Infectious diseases; Interleukin-1 Receptor-Associated Kinases - immunology; Interleukin-17 - secretion; Interleukin-6 - secretion; Interleukins; Leukocytes, Mononuclear - immunology; Ligands; Lipopolysaccharides; Medical sciences; Microbiology; Miscellaneous; Monoclonal antibodies; Monocytes; NF-kappa B - immunology; Small interfering RNA; Toll like receptors; Toll-Like Receptor 2 - immunology; Viral Core Proteins - immunology; Virology; VIRUSES; Virus; Infection; Toll like receptor 2; Toll like receptor; Flaviviridae; Hepatitis C virus; Hepacivirus; Protein
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1086/655812

Background. Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. Methods. Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. Results. TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-κB activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infected patients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infected patients results in impaired production of interleukin 17 by naive CD4+ T cells in the presence of TLR ligands. Conclusions. Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.