TAK1 kinase signaling regulates Nrf2 and intestinal homeostasis

Abstract

Inflammatory bowel disease is a chronic disease that causes inflammation of the intestine, and is one of the major health problems in the US. However, effective treatments remain to be explored. Understanding the mechanism of intestinal inflammation and damage will aid in effective treatments. TGF‐β activated kinase 1 (TAK1), which is a member of the MAPKKK and is known to be activated by many different stressors and cytokines. We have previously shown that TAK1 deficiency in the intestinal epithelium causes oxidative damage including cell death and loss of paneth cells, which resemble IBD pathology. However, it was not known the mechanism of how reactive oxygen species (ROS) are accumulated and paneth cells are depleted. We tested a hypothesis that TAK1 signaling prevents commensal bacteria‐induced ROS. We found that loss of bacteria or ablation of TLR signaling by MyD88 knockout could rescue the ROS accumulation in TAK1 deficient intestinal epithelium, while either of them could not restore the loss of paneth cells. We also identified that TAK1 modulates the stability of an antioxidant transcription factor Nrf2. These results suggest that TAK1 regulation of Nrf2 is important for elimination of bacteria‐induced ROS in the intestine. Activation of TAK1 may be a possible new approach to reduce oxidative damage in the intestine. We are currently investigating the molecular mechanism of how TAK1 regulates paneth cells.