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Title: Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice

item WANG, AN-JIANG - University Of Maryland
item Smith, Allen
item LI, YANFEI - University Of Maryland
item Urban, Joseph
item THIRUMALAI, RAMALINGAM - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item WYNN, THOMAS - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item LU, NONGHUA - Nanchang University, Nanchang, China
item SHEA-DONOHUE, TEREZ - University Of Maryland
item YANG, ZHONGHAN - Sun Yat-Sen University
item ZHAO, AIPING - University Of Maryland

Submitted to: Cell & Bioscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/1/2014
Publication Date: 11/26/2014
Citation: Wang, A., Smith, A.D., Li, Y., Urban Jr, J.F., Thirumalai, R.R., Wynn, T., Lu, N., Shea-Donohue, T., Yang, Z., Zhao, A. 2014. Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice. Cell & Bioscience. DOI: 10.1186/2045-3701-4-72.

Interpretive Summary: Inflammatory bowel disease (IBD), a term that includes both ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic relapsing inflammation of the intestine leading to diarrhea and abdominal pain. It is estimated that some 1.4 million Americans suffer from IBD. There is no cure for IBD and the relapsing course of the disease requires extended patient care with progressive medical or surgical interventions to induce remission. It is generally believed that IBD results from the combination of alterations in the microbial flora, a genetic predisposition, and a dysregulated immune response. Excessive cytokine responsiveness is a well recognized pathogenic factor important for IBD. IL-25 is a specific cytokine capable of inhibiting pro-inflammatory cytokine responses that are implicated in various types of autoimmune diseases. IL-25 also has potent immune modulating activities in innate immunity and dysregulated innate immunity plays a dominant role in pathogenesis of IBD, the current study investigated whether endogenous IL-25 contributes to the development of colonic inflammation using a model of dextran sulfate sodium (DSS)-induced colitis in mice. Results from this study showed a reduced colitis in mice genetically lacking IL-25 after exposed to DSS, thus providing genetic evidence that endogenous IL-25 has a pro-inflammatory role in the development of colitis. These studies inform scientists and nutritionists interested in markers of intestinal inflammation and the factors responsible for maintaining health and reducing the intensity of inflammation and disease.

Technical Abstract: IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote Th2 while suppressing Th1 and Th17 cytokine responses. We investigated the contribution of endogenous IL-25 to DSS-induced colitis in mice. Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25 deficient (-/-) mice as compared to wild-type (WT) mice after exposed to acute DSS. Histological examination showed that dextran sulfate sodium (DSS)-treated IL-25-/- mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not IL-25-/- mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25-/- compared to WT mice. IL-25-/- mice were also partially protected from chronic DSS challenge especially during the first two cycles of DSS exposure, and exogenous IL-25 up-regulated expression of IL-33 and several pro-inflammatory cytokines in T84 colonic epithelial cells. In contrast to IL-25-/- mice, IL-13-/- mice were more susceptible to DSS-induced colitis. These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is not mediated by IL-13 but likely through induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells.