title: Hepatitis C virus infection induces inflammatory cytokines and chemokines mediated by the cross talk between hepatocytes and stellate cells.
abstract: Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis, and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By coculturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV-infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β. Moreover, we found that this effect was mediated by IL-1α, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) β mRNA, and HSC-dependent IL-1α production contributed to the stimulation of C/EBPβ target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knockdown of mRNA for C/EBPβ in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC conditioned medium required a yet to be identified postentry event during productive HCV infection. The cross talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases.
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan. lbnishitsuji@hospk.ncgm.go.jp
authors.forename: Hironori
authors.initials: H
authors.lastname: Nishitsuji
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Saneyuki
authors.initials: S
authors.lastname: Ujino
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaku
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006526:Hepatitis C / Q000150:complications / Q000276:immunology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D034741:RNA, Small Interfering