title: Nonstructural proteins 4A and 4B of hepatitis C virus transactivate the interleukin 8 promoter.
abstract: Interleukin 8 (IL-8) is induced in many cell types by various stimuli including virus infection. It was reported that nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) was involved in induction of IL-8 expression at both mRNA and protein levels in cultured human cells. In this study, we aimed to determine whether or not another HCV protein(s) transactivates the IL-8 gene expression, by means of an IL-8 promoter-driven luciferase reporter assay and measurement of endogenous IL-8 mRNA and secreted IL-8 protein levels. We observed that NS4B, and NS4A to a lesser extent, significantly transactivated the IL-8 promoter, which resulted in enhanced production of IL-8 protein. Also, the IL-8 expression was augmented in Huh-7 cells harboring an HCV subgenomic RNA replicon, compared with the control cells. Deletion mutational analysis of the IL-8 promoter revealed the possible involvement of the transcription factor AP-1 in both NS4A- and NS4B-mediated IL-8 gene activation. In addition, the IL-8 gene activation by NS4B, but not that by NS4A, was likely to involve NF-kappaB and/or NFIL-6. The degree of the transactivation by NS4B and NS4A varied with different human cell lines, with HeLa cells showing the strongest activation followed by Huh-7 cells, and with HepG2 cells exhibiting a marginal level of activation. Taken together, our present results suggest the possibility that NS4B and NS4A play an important role in inducing the IL-8 gene expression under certain cellular conditions, which might be one of the strategies to establish persistent HCV infection.
authors.affiliation: Division of Microbiology, Kobe University Graduate School of Medicine, Hyogo, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kadoya
authors.forename: Motoko
authors.initials: M
authors.lastname: Nagano-Fujii
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakazono
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012093:Replicon / Q000235:genetics; D015533:Transcriptional Activation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D004279:DNA, Viral; D016209:Interleukin-8; C093542:NS4 protein, hepatitis C virus; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins