Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer.
Wan, Lei a,b,c,*; Lin, Cheng-Wen d; Lin, Ying-Ju c,e; Sheu, Jim J.C. a,b; Chen, Bing-Hung f; Liao, Chiu-Chu a; Tsai, Yuhsin b; Lin, Wei-Yong a; Lai, Chih-Ho g; Tsai, Fuu Jen a,b,c,*
[Article] Journal of Cellular & Molecular Medicine. 12(3):876-888, June 2008.

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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-1[beta] 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.

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