Gadd45β promotes regeneration after injury through TGFβ-dependent restitution in experimental colitis

Dysregulated immune responses and impaired function in intestinal epithelial cells contribute to the pathogenesis of inflammatory bowel disease (IBD). Growth arrest and DNA damage-inducible 45 beta (Gadd45β) has been implicated in the pathogenesis of various inflammatory symptoms. However, the role of Gadd45β in IBD is completely unknown. This study aimed to evaluate the role of Gadd45β in IBD. Gadd45β-KO mice exhibited drastically greater susceptibility to dextran sulfate sodium (DSS)-induced colitis and mortality than C57BL/6J mice. Bone marrow transplantation experiments revealed that Gadd45β functions predominantly in the intestinal epithelium and is critical during the recovery phase. Gadd45β regulates the TGF-β signaling pathway in colon tissue and epithelial cells by inhibiting Smurf-mediated degradation of TGF-β receptor type 1 via competitive binding to the N-terminal domain of Smad7. Furthermore, these results indicate that the Gadd45β-regulated TGF-β signaling pathway is involved in wound healing by enhancing epithelial restitution. These results expand the current understanding of the function of Gadd45β and its therapeutic potential in ulcerative colitis. A signaling molecule that prevents inflammatory damage in an animal model of ulcerative colitis offers a promising therapeutic target. The molecular drivers of this form of inflammatory bowel disease remain poorly understood, but the associated damage to the intestinal epithelium is primarily due to uncontrolled immune cell activity. Jung Hwan Hwang of the Korea Research Institute of Bioscience and Biotechnology, Daejeon, and coworkers have now demonstrated that a protein called Gadd45β helps to reduce inflammatory damage to the epithelial barrier. They showed that a mouse model of chemically induced ulcerative colitis exhibited more severe disease symptoms and higher mortality when these animals also lacked Gadd45β. This protein is generally known to modulate immune cell activity response, but in this disease model, the authors primarily observed activity within intestinal epithelial cells, where it appears to facilitate wound healing.