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‐α and IFN‐β 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‐α or IFN‐β 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‐α or IFN‐β significantly enhanced the stimulatory effect of IL‐1β on production of IL‐1Ra. The present study suggests a novel function of IFN‐α and IFN‐β signalling in human hepatocytes. Our results provide evidence for the mechanism how IFN‐α and IFN‐β modulate inflammatory responses through activation of STAT6 and production of secreted IL‐1Ra.