Protective function of DUSP4 in DSS-induced colitis

Abstract

Abstract Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. The mitogen-activated protein kinase (MAPK) signalling, an evolutionary conserved cell signalling pathway, is associated with IBD. MAPKs comprises ERK, P38, and JNK, which are activated by upstream MKKs and MKKKs, and are inactivated by dual specificity phosphatases (DUSPs). DUSP4 (MPK2) is a member of DUSP protein family and was found to be involved in various physiological processes. However the role of DUSP4 in IBD is yet to be examined. In this study, we utilized DSS-induced colitis mouse model to investigate the function of DUSP4 in this disease. We found that DUSP4 knockout (KO) mice were more susceptible to DSS-induced colitis, which was demonstrated by more weight loss and higher histological score than wild-type (WT) mice. Consistently, expression of inflammatory cytokines, including IL-6, TNF-α, IL-17A, and CXCL-1, was enhanced in both proximal and distal colon of DUSP4 KO mice compared to WT mice. Moreover, excessive CD8+ and CD4+ cells, especially IL-17A-expressing CD4+ T cells, were identified in the mesenteric lymph node (mLN) of the KO mice. Together, these results demonstrated that deficiency of DUSP4 resulted in increased inflammation in the gut in response to DSS.