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

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.

Acute blockade of IL-25 in a colitis associated colon cancer model leads to increased tumor burden

“…Consistent with this, when IL-25 −/− mice were used in another model of helminth infection, Nippostrongylus brasiliensis , the protective role of IL-25 was dependent on its ability to induce type-2 cytokine production 32 . Models of colitis have shown IL-25 to be either protective 33 or promoting 34 of inflammation in the gastrointestinal tract. However, when IL-25 −/− mice were used in the colitis associated colon cancer model, we found no difference in the ultimate outcome.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…144 A recent study showed that IL-17E was produced by intestinal epithelial cells during acute colitis and that mice deficient in IL-17E were protected from DSS-induced colitis. 65,146 Furthermore, neutralizing IL-17E or IL-17RB with antibodies ameliorates the onset of oxazolone-induced colitis. 147 These contradictory results suggest that endogenous IL-17E signaling rather than the exogenous delivery of IL-17E might be pathogenic and contribute to intestinal inflammation.…”

IL-17E (IL-25) and IL-17A Differentially Affect the Functions of Human Keratinocytes

“…IL-17E, also known as IL-25, possesses the lowest homology with IL-17A and is also produced by epithelial cells (Angkasekwinai et al, 2007;Johnston et al, 2013;Xu and Dong, 2017). Although initially thought to exclusively participate in T helper type 2 responses in the gut and lung (Angkasekwinai et al, 2007;Ballantyne et al, 2007;Caruso et al, 2009;Hvid et al, 2011;Owyang et al, 2006;Wang et al, 2014;Xu and Dong, 2017), IL-17E was demonstrated recently to be implicated in several skin inflammatory disorders. In atopic dermatitis, IL-17E was shown to impair the proper epidermal barrier formation (Deleuran et al, 2012;Hvid et al, 2011).…”