Abstract
IL‐23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL‐17 and IL‐22. Recently, we demonstrated that Notch signaling drives IL‐22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A‐induced hepatitis. In this study, we investigated the role of IL‐23 in hepatitis using IL‐23p19‐ and IL‐17‐deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL‐23, IL‐22, IL‐17, IFN‐γ and TNF‐α. In IL‐23p19‐deficient mice, exacerbated hepatitis was observed and serum IL‐22 and IL‐17 levels were greatly reduced, whereas in IL‐17‐deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL‐22 protected p19‐deficient mice from hepatitis, whereas the injection of exogenous IL‐23 significantly increased the serum levels of not only IL‐22 but also IL‐17, and less effectively protected against hepatitis in IL‐17‐dependent and ‐independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL‐22 production in response to Con A and IL‐23 in liver mononuclear cells. These results suggest that IL‐23 plays a protective role in hepatitis through IL‐22 production and also a pathological role via IL‐17‐dependent and ‐independent mechanisms.