Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer.
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.
Wan
Lei
L
Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, Taiwan. leiwan@www.cmuh.org.tw
Lin
Cheng-Wen
CW
Lin
Ying-Ju
YJ
Sheu
Jim J C
JJ
Chen
Bing-Hung
BH
Liao
Chiu-Chu
CC
Tsai
Yuhsin
Y
Lin
Wei-Yong
WY
Lai
Chih-Ho
CH
Tsai
Fuu Jen
FJ
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*
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