Correlation of type I, -II and -III interferon expression in the liver with clinical and viral parameters in chronic HCV infection

Abstract

Aims: It has been reported that expression of Interferon-stimulated genes (ISGs) in the liver of patients with chronic hepatitis C (HCV) correlates with sustained virological response (SVR) to antiviral treatment. It is not well understood by which IFNs these ISGs are induced or whether expression of IFNs is associated with virological parameters or therapy outcome. Methods: HCV load and IFNs (-α, -β, -γ, -λ [IL28a, IL28b, IL29], and IFN-ω) were determined in liver biopsies of 60 HCV patients prior to antiviral therapy and in 10 non-HCV patients by qt RT-PCR. Clinical parameters including HCV load in serum and liver transaminases were analyzed 36 hours, 4 weeks and 12 weeks after initiation of therapy. Results: IFN-α, IFN-β and -γ expression levels could be detected in biopsies of 55%, 73% or 88% of HCV patients, respectively. IFN-α expression was not correlated to clinical parameters like HCV load, genotype, transaminases, fibrosis staging, inflammation grading or expression of ISGs while expression of IFN-β was associated with lower expression levels of ISGs (p<0.002). Higher expression levels of IFN-γ were found in patients with elevated liver transaminases (p<0,003, ALT) and with higher stages of fibrosis (p<0.007). No correlations were found between IFN-γ expression and inflammation grading, HCV serum load, genotype, antiviral response or ISG expression levels. IFN-λ and –ω expression was detectable in less than 10% of HCV positive liver biopsies. Conclusions: Prognostically relevant hepatic expression of ISGs in HCV patients is primarily correlated to the expression of type I and II IFNs while type III IFNs are only rarely detectable. Hepatocyte damage is associated with the presence of IFN-γ. None of the IFNs is correlated to the clinical and virological response to therapy which leads us to hypothesize that the unfavorable induction of ISGs may be due to „hyper-responsiveness“ of the target cells to IFNs rather than overproduction of IFNs.