The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut

Abstract

We used mice deficient in each of the eight types and subtypes of prostanoid receptors and examined the roles of prostanoids in dextran sodium sulfate–induced (DSS-induced) colitis. Among the prostanoid receptor–deficient mice, only EP4-deficient mice and not mice deficient in either DP, EP1, EP2, EP3, FP, IP, or TP developed severe colitis with 3% DSS treatment, which induced only marginal colitis in wild-type mice. This phenotype was mimicked in wild-type mice by administration of an EP4-selective antagonist (AE3-208). The EP4 deficiency impaired mucosal barrier function and induced epithelial loss, crypt damage, and aggregation of neutrophils and lymphocytes in the colon. Conversely, administration of an EP4-selective agonist (AE1-734) to wild-type mice ameliorated severe colitis normally induced with 7% DSS, while that of AE3-208 suppressed recovery from colitis and induced significant proliferation of CD4+ T cells. In vitro AE3-208 enhanced and AE1-734 suppressed the proliferation and Th1 cytokine production of lamina propria mononuclear cells from the colon. DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice. We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response

The COX-2 inhibitor, rofecoxib, ameliorates dextran sulphate sodium induced colitis in mice

“…Recent reports have shown that exogenously applied PGE 2 attenuated DSS-induced colitis and promoted epithelial proliferation [25,34,35] suggesting that endogenous PGE 2 is the mediator of mucosal protection. PGE 2 exerts anti-inflammatory effects including suppression of neutrophil function or prevention of mast cell degranulation [36] as well as suppressor T-cell induction and inhibition of the production and release of proinflammatory cytokines such as TNF-a, IL-1b and IL-12 by macrophages and neutrophils [35].…”

“…PGE 2 exerts anti-inflammatory effects including suppression of neutrophil function or prevention of mast cell degranulation [36] as well as suppressor T-cell induction and inhibition of the production and release of proinflammatory cytokines such as TNF-a, IL-1b and IL-12 by macrophages and neutrophils [35]. Also PGE 2 plays a major role in the generation of the epithelial crypts after DSS-induced intestinal damage in mice [37].…”

Inflammatory bowel disease, past, present and future: lessons from animal models

“…Recently, many groups have examined the recovery phase after a single administration of DSS. 93,[132][133][134][135][136] Both acquired and innate immune responses have been implicated in the recovery phase, 93,132 and the epithelial cell regeneration observed during the recovery phase resembles that observed in chronic colitis. 135 Therefore, this recovery model may be useful for studying the wound healing process (epithelial regeneration) and the linkage between innate and acquired immune responses.…”

Nutrigenomics in the whole-genome scanning era: Crohn’s disease as example

“…They showed that these variants correlated with increased expression levels of the nearest gene, PTGER4, which encodes the prostaglandin receptor EP4. Prostaglandin E4 is proinflammatory, triggering the activation of NF-kB, and knockout mouse studies have shown that PTGER4 is involved in the development of colitis [51]. Prostaglandin receptor EP4 is also important in the activation of T reg cells [52 -54] and disruption of this process could contribute to the loss of tolerance to commensal bacteria and to the inflammation that is the hallmark of CD.…”