Up-regulation of colonic Th1/Th17 cytokines is associated with increased severity of experimental colitis in mice lacking microsomal prostaglandin E synthase-1

Abstract

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) H₂ to PGE₂. PGE₂ 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 (TNF-α) 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 PGE₂ plays a protective role in IBD, partly by regulating the production of Th1/Th17 cytokines in colon.