Impaired interferon type I signalling in the liver modulates the hepatic acute phase response in hepatitis C virus transgenic mice

BACKGROUND/AIMS: The immunomodulatory active hepatitis C virus (HCV) has been shown to interfere with antiviral interferon (IFN) type I functions. The aim of the study was to determine whether further basic innate immunologic functions are influenced by HCV. METHODS: The acute phase response (APR) was induced in HCV transgenic (tg) mice and C57BL/6J control mice using lipopolysaccharide. Activation of transcription factors, mRNA expression and production of cytokines and acute phase proteins (APP) were determined. IFN type I and tumor necrosis factor (TNF) alpha signalling were investigated after polyI:C or TNF-alpha treatment. RESULTS: HCV tg mice showed an attenuated APR: hepatic activation of nuclear factor kappa B (NFkappaB) and interferon-stimulated gene factor 3 (ISGF3), hepatic expression of interleukin (IL) 6, IL-10, and IFN-gamma mRNA, serum concentrations of IL-6 and IFN-gamma and production of type II acute phase proteins were reduced compared to wild-type mice. While no differences in NFkappaB activation could be detected after TNF-alpha injection, HCV tg mice showed reduced activation of ISGF3 and reduced transactivation of IFN target genes after polyI:C treatment. CONCLUSIONS: Besides antiviral defence mechanisms, interruption of IFN type I signalling by HCV modulates the APR which is aimed at a variety of pathogens.