title: Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer.
abstract: The biological activities of type I interferons (IFNs) are mediated by their binding to a heterodimer receptor complex (IFNAR1 and IFNAR2), resulting in the activation of the JAK (JAK1 and TYK2)-STAT (1, 2, 3, 5 isotypes) signalling pathway. Although several studies have indicated that IFN-alpha and IFN-beta can activate complexes containing STAT6, the biological role of this activation is still unknown. We found that exposure of hepatoma cells (HuH7 and Hep3B) to IFN-alpha or IFN-beta led to the activation of STAT6. Activated STAT6 in turn induced the formation of STAT2: STAT6 complexes, which led to the secretion of IL-1Ra. The activation of STAT6 by type I IFN in hepatocytes was mediated by JAK1 and Tyk2. In addition, IFN-alpha or IFN-beta significantly enhanced the stimulatory effect of IL-1beta on production of IL-1Ra. The present study suggests a novel function of IFN-alpha and IFN-beta signalling in human hepatocytes. Our results provide evidence for the mechanism how IFN-alpha and IFN-beta modulate inflammatory responses through activation of STAT6 and production of secreted IL-1Ra.
authors.affiliation: Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, Taiwan. leiwan@www.cmuh.org.tw
authors.forename: Lei
authors.initials: L
authors.lastname: Wan
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Lin
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lin
authors.forename: Jim J C
authors.initials: JJ
authors.lastname: Sheu
authors.forename: Bing-Hung
authors.initials: BH
authors.lastname: Chen
authors.forename: Chiu-Chu
authors.initials: CC
authors.lastname: Liao
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Tsai
authors.forename: Wei-Yong
authors.initials: WY
authors.lastname: Lin
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.forename: Fuu Jen
authors.initials: FJ
authors.lastname: Tsai
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019281:Dimerization; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010766:Phosphorylation; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*
chemical_list: C507763:IL1RN protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D050795:STAT2 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016899:Interferon-beta