Abstract
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.
Highlights
Inflammatory bowel disease (IBD) manifests as chronic intestinal inflammation and structural and functional disruptions of the gastrointestinal tract[1]
We investigated the role of Gadd45β in intestinal homeostasis using rodents lacking Gadd45β and control wild-type (WT) C57BL/6J mice to establish a dextran sulfate sodium (DSS)-induced colitis model mimicking the clinical pathogenesis of ulcerative colitis (UC)
Gadd45β-positive cells were more frequent in the colon and ileum than in the kidneys, and liver and epithelial cells were prominently stained, suggesting a possible role for Gadd45β in the intestine (Supplementary Fig. 1c)
Summary
Inflammatory bowel disease (IBD) manifests as chronic intestinal inflammation and structural and functional disruptions of the gastrointestinal tract[1]. IBD exists in two clinical forms: Crohn’s disease (CD) and ulcerative colitis (UC). In CD, inflammation can occur in any part of the gastrointestinal tract. Ulcerative colitis is, restricted to the large intestine[2]. The incidence and prevalence of IBD have recently increased steadily in developing and developed countries;[3] its pathogenesis has remained elusive. The etiology of IBD involves multiple factors, including host genetic susceptibility, the Official journal of the Korean Society for Biochemistry and Molecular Biology
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