Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon‐based therapy in chronic hepatitis C. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Murakawa, Miyako; Asahina, Yasuhiro; Nakagawa, Mina; Sakamoto, Naoya; Nitta, Sayuri; Kusano‐Kitazume, Akiko; Watanabe, Takako; Kawai‐Kitahata, Fukiko; Otani, Satoshi; Taniguchi, Miki; Goto, Fumio; Nishimura‐Sakurai, Yuki; Itsui, Yasuhiro; Azuma, Seishin; Kakinuma, Sei; Watanabe, Mamoru
• Is Part Of: Journal of gastroenterology and hepatology. Volume 30:Issue 6(2015:Jun.)
• Page Start: 1075
• Page End: 1084
• Publication Date: 2015-06
• Subjects: Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; Liver -- Diseases -- Periodicals; Gastroenterology -- Periodicals; Liver Diseases -- Periodicals; 616.33
• DOI: 10.1111/jgh.12902
• Languages: English
• ISSNs: 0815-9319

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jgh12902-sec-0001" sec-type="section"> <title>Background and Aim</title> <p>Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near <italic>IL28B</italic> (<italic>IFN</italic><italic>λ3</italic>) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to <italic>IL28B</italic>‐unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN‐based therapy in CHC associated with SNPs near <italic>IL28B</italic>.</p> </sec> <sec id="jgh12902-sec-0002" sec-type="section"> <title>Methods</title> <p>We evaluated the basal mRNA levels and ex‐vivo induction of <italic>IFNλ</italic> expression including <italic>IFN</italic><italic>λ4</italic> in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated‐IFNα/RBV. Furthermore, we investigated the effect of <italic>IFN</italic><italic>λ4</italic> on induction of <italic>IL28B</italic> in vitro.</p> </sec> <sec id="jgh12902-sec-0003" sec-type="section"> <title>Results</title> <p>When PBMCs were stimulated with IFNα and polyinosinic–polycytidylic acid, <italic>IL28B</italic> induction was significantly lower in patients with <italic>IL28B</italic>‐unfavorable genotype (rs12979860 CT/TT) than those with <italic>IL28B</italic>‐favorable genotype (rs12979860 CC; <italic>P</italic> = 0.049). <italic>IL28B</italic> induction was lower in nonresponders than in relapsers (<italic>P</italic> = 0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. <italic>IFN</italic><italic>λ4</italic> mRNA was detected in 12 of 26 patients with <italic>IL28B</italic>‐unfavorable SNP, and <italic>IFN</italic><italic>λ4</italic> expression was associated with lower <italic>IL28B</italic> induction in patients with <italic>IL28B</italic>‐unfavorable genotype (<italic>P</italic> = 0.04) and nonresponse to IFNα therapy (<italic>P</italic> = 0.003). Overexpression of <italic>IFN</italic><italic>λ4</italic> suppressed <italic>IL28B</italic> induction and promoter activation.</p> </sec> <sec id="jgh12902-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Impaired induction of <italic>IL28B</italic>, related to <italic>IFN</italic><italic>λ4</italic> expression in PBMCs of <italic>IL28B</italic>‐unfavorable patients, is associated with nonresponse to IFNα‐based therapy for hepatitis C viral infection.</p> </sec> </abstract>