The aryl hydrocarbon receptor is a novel negative regulator of interleukin-17-mediated signaling and inflammation in vitro.

Interleukin (IL)-17 plays a critical role in the pathogenesis of inflammation and autoimmune diseases. The aryl hydrocarbon receptor (AHR) is a transcription factor responsible for the elimination of xenobiotic chemicals. However, it remains unknown whether AHR is involved in IL-17 signaling. Here, we demonstrate that knockdown of AHR significantly enhances, while overexpression or activation of AHR inhibits IL-17-induced inflammation in Hela cells. AHR specifically suppresses IL-17-induced p38 activation, and inhibition of p38 activity markedly reverses the effect of AHR knockdown on IL-17-induced inflammation. Mechanistically, AHR physically interacts with TAK1 and mitogen-activated protein kinase kinase 3/6 (MKK3/6) and disrupts TAK1-MKK3/6 interaction, leading to impaired IL-17 signaling. Thus, our study indicates that AHR negatively regulates IL-17-mediated signaling and inflammation at least partially through interfering with the interaction between TAK1 and MKK3/6.