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.

Multiple sclerosis (MS) is one of the most common demyelinating diseases. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation and immune responses by converting prostaglandin (PG) H 2 to PGE 2 . PGE 2 is highly produced in the cerebrospinal fluid of patients with MS. However, the role of mPGES-1 in MS has not been fully elucidated yet. In this study, we demonstrate the role of mPGES-1 in demyelination and motor dysfunction induced by cuprizone, one of the well established models of MS. Demyelination in the brain was induced in mice lacking mPGES-1 (mPGES-1 −/− mice) and wild-type (WT) mice by feeding ad libitum with a powdered diet containing 0.2% cuprizone for 6 weeks under specific pathogen free condition. The expression of mPGES-1 in the brain was determined by real-time PCR. The cuprizone-induced demyelination was assessed by a myelin staining with coronal brain sections, and motor dysfunction was evaluated by the rotarod test. Cuprizone up-regulated the expression of mPGES-1 mRNA in the brain of WT mice. Interestingly, mPGES-1 −/− mice exhibited lower degree of demyelination compared to WT mice. In addition, mPGES-1 gene deletion or COX-2 selective inhibitor celecoxib reduced cuprizone-induced motor dysfunction. These data indicate that COX-2/mPGES-1/PGE 2 system contributes to the pathophysiology of MS and open possible novel therapeutic approaches for MS.

Background: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is one of the most common intestinal disorders. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in the inflammatory response by converting prostaglandin (PG) H 2 to PGE 2 . PGE 2 is highly produced in the inflamed mucosa of patients with IBD. However, the role of mPGES-1 in IBD has not been fully elucidated yet. In this study, we demonstrate the role of mPGES-1 in an experimental colitis induced by dextran sulfate sodium (DSS), one of the well established models of IBD.Methods: Colitis was induced in mice lacking mPGES-1 (mPGES-1 -/mice) and wild-type (WT) mice by administering DSS orally in drinking water for 7 days under specific pathogen free condition. The expression and localization of mPGES -1 in colon were determined by real-time PCR, western blotting and immunohistochemistry. Colonic inflammation was assessed based on the changes of body weight, stool consistency, signs of fecal blood, total colon length and histological features. The expression levels of interferon-γ (IFN-γ), intereukin-17A (IL-17A) and tumor necrosis factor-α (TNFα) in inflamed colon were determined by real-time PCR. Results: The expression of mPGES-1 was highly induced on both mRNA and protein levels in the colon of WT mice after DSS administration. In addition, mPGES-1 protein was localized in the colonic mucosal epithelium and underlying connective tissues. The mPGES-1 -/mice exhibited massive loss of body weight, severe symptoms of loose stool and signs of fecal blood compared to those of WT mice during administration of DSS. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1 -/mice. These abnormalities consistent with the colitis observed in mPGES-1 -/mice were associated with higher expression levels of colonic T-helper (Th) 1 and Th17 cytokines including IFN-γ and IL-17A. The colonic expression of TNF-α, the most prominent target of human IBD therapies, was also highly up-regulated in mPGES-1 -/mice in response to DSS treatment. Conclusion: mPGES-1 and its derived PGE 2 plays a protective role in IBD, partly by regulating the production of Th1/Th17 cytokines in colon.