Abstract
Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology. Here we demonstrate that mice deficient for REGγ, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REGγ's function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REGγ exacerbates local inflammation and promotes a reciprocal regulatory loop with NFκB involving ubiquitin-independent degradation of IκBɛ. Additional deletion of IκBɛ restored colitis phenotypes and inflammatory gene expression in REGγ-deficient mice. In sum, this study identifies REGγ-mediated control of IκBɛ as a molecular mechanism that contributes to NFκB activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.
Highlights
Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology
Histological analysis of colitis tissues from day 7 diseased mice by haematoxylin and eosin (H&E) staining revealed that REGg À / À mice had less crypt damage, ulceration and inflammation than WT littermates (Fig. 1e), as described in semi-quantitative scoring of histopathology (Fig. 1f,g). These results demonstrate that REGg-deficiency can increase resistance to experimental colitis
In this study, we demonstrate that the proteasome activator REGg is a regulatory factor involved in bowel inflammation and cancer development (CAC) development in dextran sodium sulfate (DSS) models
Summary
Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology. We demonstrate that mice deficient for REGg, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-associated cancer in dextran sodium sulfate model. This study identifies REGg-mediated control of IkBe as a molecular mechanism that contributes to NFkB activation and promotes bowel inflammation and associated tumour formation in response to chronic injury. 8 Department of Orthopedic Oncology, Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic relapsing intestinal inflammation. Genome-wide searches for IBD susceptibility loci have successfully identified 163 gene loci that contribute to disease susceptibility[3] Among these genes are the nuclear factor kappa B (NFkB) family members Rel ( known as c-Rel) and Rel A (refs 4,5), known as key regulators of inflammatory gene expression. For IkBe, the constitutive degradation pathway has not been characterized to the best of our knowledge
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