Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C

Background and AimInterferon (IFN) plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFN3) are strongly associated with treatment response to IFN therapy in chronic hepatitis C (CHC) patients. Recently, IFN4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B. MethodsWe evaluated the basal mRNA levels and ex-vivo induction of IFN expression including IFN4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFN/RBV. Furthermore, we investigated the effect of IFN4 on induction of IL28B in vitro. ResultsWhen PBMCs were stimulated with IFN and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P=0.049). IL28B induction was lower in nonresponders than in relapsers (P=0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFN4mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFN4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFN therapy (P=0.003). Overexpression of IFN4 suppressed IL28B induction and promoter activation. ConclusionsImpaired induction of IL28B, related to IFN4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFN-based therapy for hepatitis C viral infection.