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Hepatitis C virus core protein interacts with fibrinogen‐β and attenuates cytokine stimulated acute‐phase response
Author(s) -
AitGoughoulte Malika,
Banerjee Arup,
Meyer Keith,
Mazumdar Budhaditya,
Saito Kousuke,
Ray Ratna B.,
Ray Ranjit
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23502
Subject(s) - transfection , microbiology and biotechnology , small interfering rna , hepatitis c virus , promoter , biology , hepatocyte , gene expression , cell culture , gene , virus , virology , in vitro , biochemistry , genetics
Fibrinogen‐β (FBG‐β), an important acute‐phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here we identified FBG‐β as a hepatitis C virus (HCV) core interacting protein by screening a human liver complementary DNA (cDNA) library using mammalian two‐hybrid analysis. An association between FBG‐β and HCV core protein was verified by confocal microscopy and coimmunoprecipitation from the transfected human hepatocyte (Huh‐7) cell line. HCV core or genomic RNA transfected Huh‐7 cells modestly increased FBG‐β protein expression when compared to the basal level in control hepatocytes. Transfection of HCV core or full‐length (FL) gene into Huh‐7 cells up‐regulated basal FBG‐β promoter activity. Exogenous addition of IL‐6 stimulates FBG‐β promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL‐6‐stimulated FBG‐β promoter activation. Inhibition of endogenous FBG‐β expression following introduction of small interfering RNA (siRNA) into cells displayed a gain of function of promoter regulation by HCV core protein. Further studies suggested that HCV core gene expression in stable transfectants of Huh‐7 cells resulted in a basal up‐regulation of FBG‐β and other APPs. However, treatment with cytokines, interleukin‐6 (IL‐6), or tumor necrosis factor‐α repressed FBG‐β and other acute‐phase response (APR) genes. Conclusion: Our results reveal that the core/FBG‐β interaction may act as a regulatory feedback, allowing repression of IL‐6‐stimulated APR genes. Together, these data suggested a network of interactions between HCV core and the hepatic APR genes, and may contribute to impaired innate immunity for viral persistence. (H EPATOLOGY 2010.)