Abstract
BackgroundIL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25.ResultsMice 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−/− mice compared to WT mice after exposure to acute DSS. Histological examination showed that 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 in the 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 2 cycles of DSS exposure. In contrast to IL-25−/− mice, IL-13−/− mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.ConclusionsThese data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.
Highlights
MethodsMice deficient in IL-13 (IL-13−/−) were generated in a mixed background [42] and managed by Taconic at the National Institutes of Allergy and Infectious Diseases
IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses
Given that IL-25 has potent immune modulating activities especially in innate immunity and that dysregulated innate immunity plays a dominant role in pathogenesis of Inflammatory bowel disease (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
Summary
Mice deficient in IL-13 (IL-13−/−) were generated in a mixed background [42] and managed by Taconic at the National Institutes of Allergy and Infectious Diseases. These mice were backcrossed to C57BL/6 mice for at least 10 generations after being received, which is considered fully congenic and C57BL/6 WT mice were used as the controls. All mice were used at the age of 10 to 14 week old and all studies were conducted with institutional approval from both the University of Maryland, Baltimore and the USDA Beltsville Area Animal Care and Use Committees (protocol #13-003) in accordance with principles set forth in the Guide for Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, Health and Human Services Publication (National Institutes of Health 85–23, revised 1996)
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