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.

Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4

“…PTGER4 is a strong candidate gene for CD, as it is known that knock-out mice develop severe colitis upon dextran sodium sulphate treatment, unlike mice deficient in any of the seven other types of prostanoid receptors. Increased susceptibility to colitis is also observed in wild-type mice administered an EP4-selective antagonist, while EP4-selective agonists are protective [14]. We observe in particular that the CD susceptibility allele at marker rs4495224 is associated with increased PTGER4 transcript levels in lymphoblastoid cell lines.…”

Crucial Role of Macrophage Selenoproteins in Experimental Colitis

“…A prominent role for PGE 2 in UC was suggested by studies where increased incidences of active UC (36, 41, 42) was associated with increasing PGE 2 concentrations leading to the activation of the PGE 2 -TNFα axis (43, 44). However, PGE 2 is also essential in the suppression of colitis, as shown in the EP4 −/− mice, where increased sensitivity towards experimental colitis was seen (12). Thus, Se status appears be a key regulator of the levels of PGE 2 by 15-PGDH-dependent metabolism to 15-keto-PGE 2 and 13,14-dihydro-15-keto-PGA 2 to alleviate inflammation as well as promote resolution.…”

“…PGD 2 -derived CyPG metabolites exert significant anti-inflammatory effects (8, 9), whereas elevated levels of PGE 2 and TNF-α have been linked to the promotion of inflammation, ulceration, edema, and pain (10, 11). Thus, inhibition of PGE 2 could be a double-edged sword because of its pro-angiogenic role in the maintenance of mucosal integrity in experimental colitis (12) and its link to the activation of resolution by stimulating the eicosanoid class switching to anti-inflammatory and pro-resolving mediators in human leukocytes (13). The mice deficient in PGE 2 receptor (EP) subtype EP4 (12) were found to develop experimental colitis and treatment with an EP4 agonist ameliorated colitis in wild-type mice (12).…”

“…Thus, inhibition of PGE 2 could be a double-edged sword because of its pro-angiogenic role in the maintenance of mucosal integrity in experimental colitis (12) and its link to the activation of resolution by stimulating the eicosanoid class switching to anti-inflammatory and pro-resolving mediators in human leukocytes (13). The mice deficient in PGE 2 receptor (EP) subtype EP4 (12) were found to develop experimental colitis and treatment with an EP4 agonist ameliorated colitis in wild-type mice (12). These studies suggest a pleiotropic role for PGE 2 , where the control of PGE 2 production and catabolism may have a significant bearing on the pathophysiology of UC.…”

Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration

“…PGE2 similarly supports the expansion of human colon stem cells in cell culture (18). And, in a model of murine colitis, colon injury was exacerbated by a COX enzyme antagonist but was ameliorated by treatment withdmPGE2 (19). …”