Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute-phase response.
Fibrinogen-beta (FBG-beta), an important acute-phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here we identified FBG-beta 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-beta 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-beta 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-beta promoter activity. Exogenous addition of IL-6 stimulates FBG-beta promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL-6-stimulated FBG-beta promoter activation. Inhibition of endogenous FBG-beta 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-beta and other APPs. However, treatment with cytokines, interleukin-6 (IL-6), or tumor necrosis factor-alpha repressed FBG-beta and other acute-phase response (APR) genes.


CONCLUSIONS
Our results reveal that the core/FBG-beta 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.
Ait-Goughoulte
Malika
M
Department of Internal Medicine, Saint Louis University, St Louis, MO 63104, USA.
Banerjee
Arup
A
Meyer
Keith
K
Mazumdar
Budhaditya
B
Saito
Kousuke
K
Ray
Ratna B
RB
Ray
Ranjit
R
D000210:Acute-Phase Reaction / Q000188:drug therapy*; D002460:Cell Line; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D025941:Protein Interaction Mapping; D021122:Protein Subunits / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D014758:Viral Core Proteins / Q000378:metabolism*
D015850:Interleukin-6; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D005340:Fibrinogen