Activation of TGF ‐ β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

The etiology and mechanisms for inflammatory bowel disease ( IBD ) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD . We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF ‐ β activated Kinase 1 ( TAK 1), a central regulator of cellular inflammatory actions. Activation of TAK 1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis ( UC ) or Crohn's disease ( CD ) as well as in DSS ‐induced and spontaneous IBD in mice. The role of TAK 1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)‐7‐Oxozeaenol, a highly selective pharmacological inhibitor of TAK 1. We found hyper‐activation of TAK 1 in patients with UC or CD and in murine models of IBD . Pharmacological inhibition of TAK 1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD . We demonstrated that at the early phase of the disease activation of TAK 1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK 1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK 1 as crucial in promoting intestinal inflammation. Thus, the TAK 1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.