Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate–induced colitis in mice lacking microsomal prostaglandin E synthase-1

Abstract

Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD.

Pretreatment with IPA ameliorates colitis in mice: Colon transcriptome and fecal 16S amplicon profiling

“…Similar protective effects against LPS-induced colitis were also observed; IPA protects LPS-induced mice by activating AhR to promote IL-10 production while suppressing the gene expression of TNF-α ( 43 ). Largely consistent with our results, similar reports of the expression profile of cytokines have been found in other models of DSS-induced colitis in mice ( 44 ). Sári et al.…”

Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate Epithelial Homeostasis

“…[32][33][34][35] In colonic inflammation, mPGES-1 expression in colon was enhanced in mucosal epithelial cells and infiltrated inflammatory cells, which was associated with PGE 2 upregulation, mediating intestinal inflammation negatively as well as epidermis by inhibiting necroptosis of intestinal epithelial cells via EP4 signaling and inducing resolution of colitis. [36][37][38] PGE 2 downregulated epithelial Na-K-ATPase activity by transcriptional suppression of α1 and β1 subunits of Na-K-ATPase via EP2/EP4 and PKA activation, which suggested the involvement of PGE 2 in the malabsorption of essential nutrients in chronic enteritis. 39) prostaglandin D 2 (PGD 2 ) negatively regulated the T-helper 2 (Th2) inflammatory responses in intestinal epithelial cells through its receptor CRTH2 expressed in the intestinal stem, goblet, and tuft cells.…”

Animal models of inflammatory bowel disease: category and evaluation indexes

“…Following sampling, anatomical specimens of the intestine can be directly observed and the colon mucosal damage score can be determined based on the severity of ulcers, inflammation, and mucosal edema [ 98–102 ]. In IBD models, the colons often become shorter [ 98–100 ], accompanied by splenomegaly [ 101 , 102 ]. Optical micropathological observation is used to note pathological features such as mucosal epithelial injury, loss of crypts and goblet cells, infiltration of submucosal inflammatory cells, etc.…”