title: Kinetic differences in the induction of interferon stimulated genes by interferon-α and interleukin 28B are altered by infection with hepatitis C virus.
abstract: Several genome-wide association studies (GWAS) have identified a genetic polymorphism associated with the gene locus for interleukin 28B (IL28B), a type III interferon (IFN), as a major predictor of clinical outcome in hepatitis C. Antiviral effects of the type III IFN family have previously been shown against several viruses, including hepatitis C virus (HCV), and resemble the function of type I IFN including utilization of the intracellular Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. Effects unique to IL28B that would distinguish it from IFN-α are not well defined. By analyzing the transcriptomes of primary human hepatocytes (PHH) treated with IFN-α or IL28B, we sought to identify functional differences between IFN-α and IL28B to better understand the roles of these cytokines in the innate immune response. Although our data did not reveal distinct gene signatures, we detected striking kinetic differences between IFN-α and IL28B stimulation for interferon stimulated genes (ISGs). While gene induction was rapid and peaked at 8 hours of stimulation with IFN-α in PHH, IL28B produced a slower, but more sustained increase in gene expression. We confirmed these findings in the human hepatoma cell line Huh7.5.1. Interestingly, in HCV-infected cells the rapid response after stimulation with IFN-α was blunted, and the induction pattern resembled that caused by IL28B.
  
  
  CONCLUSIONS
  The kinetics of gene induction are fundamentally different for stimulations with either IFN-α or IL28B in hepatocytes, suggesting distinct roles of these cytokines within the immune response. Furthermore, the observed differences are substantially altered by infection with HCV.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Jilg
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.forename: Esperance A
authors.initials: EA
authors.lastname: Schaefer
authors.forename: David
authors.initials: D
authors.lastname: Wolski
authors.forename: James
authors.initials: J
authors.lastname: Meixong
authors.forename: Kaku
authors.initials: K
authors.lastname: Goto
authors.forename: Cynthia
authors.initials: C
authors.lastname: Brisac
authors.forename: Pattranuch
authors.initials: P
authors.lastname: Chusri
authors.forename: Dahlene N
authors.initials: DN
authors.lastname: Fusco
authors.forename: Stephane
authors.initials: S
authors.lastname: Chevaliez
authors.forename: Jay
authors.initials: J
authors.lastname: Luther
authors.forename: Kattareeya
authors.initials: K
authors.lastname: Kumthip
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015897:Comorbidity; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006526:Hepatitis C / Q000453:epidemiology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D050794:STAT1 Transcription Factor; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494079:STAT1 protein, human
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