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

• Published in: The Journal of clinical investigation Vol. 109; no. 7; pp. 883 - 893
• Main Authors: Kabashima, Kenji, Saji, Tomomi, Murata, Takahiko, Nagamachi, Miyako, Matsuoka, Toshiyuki, Segi, Eri, Tsuboi, Kazuhito, Sugimoto, Yukihiko, Kobayashi, Takuya, Miyachi, Yoshiki, Ichikawa, Atsushi, Narumiya, Shuh
• Format: Journal Article
• Language: English
• Published: United States 01.04.2002
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Division; Colon - drug effects; Colon - immunology; Colon - pathology; Dextran Sulfate - adverse effects; Dinoprostone - immunology; Dinoprostone - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Indomethacin - adverse effects; Inflammatory Bowel Diseases - chemically induced; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - physiopathology; Interferon-gamma - biosynthesis; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E - antagonists & inhibitors; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E - immunology; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction - immunology; Th1 Cells - immunology
• ISSN: 0021-9738
• DOI: 10.1172/jci0214459

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.