title: Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C.
abstract: OBJECTIVE
  Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-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 IL28B.
  
  
  METHODS
  We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro.
  
  
  RESULTS
  When PBMCs were stimulated with IFNα 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. IFNλ4 mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFNα therapy (P=0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation.
  
  
  CONCLUSIONS
  Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Murakawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Sayuri
authors.initials: S
authors.lastname: Nitta
authors.forename: Akiko
authors.initials: A
authors.lastname: Kusano-Kitazume
authors.forename: Takako
authors.initials: T
authors.lastname: Watanabe
authors.forename: Fukiko
authors.initials: F
authors.lastname: Kawai-Kitahata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Otani
authors.forename: Miki
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Goto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura-Sakurai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.forename: Seishin
authors.initials: S
authors.lastname: Azuma
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012333:RNA, Messenger; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human
keywords: NS3 protease inhibitor; hepatitis C virus; pegylated interferon; peripheral blood mononuclear cells; type III interferon