The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
Kenji Kabashima, Tomomi Saji, Takahiko Murata, Miyako Nagamachi, Toshiyuki Matsuoka, Eri Segi, Kazuhito Tsuboi, Yukihiko Sugimoto, Takuya Kobayashi, Yoshiki Miyachi, Atsushi Ichikawa, Shuh Narumiya
Kenji Kabashima, Tomomi Saji, Takahiko Murata, Miyako Nagamachi, Toshiyuki Matsuoka, Eri Segi, Kazuhito Tsuboi, Yukihiko Sugimoto, Takuya Kobayashi, Yoshiki Miyachi, Atsushi Ichikawa, Shuh Narumiya
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Article

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.

Authors

Kenji Kabashima, Tomomi Saji, Takahiko Murata, Miyako Nagamachi, Toshiyuki Matsuoka, Eri Segi, Kazuhito Tsuboi, Yukihiko Sugimoto, Takuya Kobayashi, Yoshiki Miyachi, Atsushi Ichikawa, Shuh Narumiya

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Induction of severe colitis by 3% DSS in EP4-deficient mice and not in m...
Induction of severe colitis by 3% DSS in EP4-deficient mice and not in mice deficient in other prostanoid receptors. (a–c) Wild-type C57BL/6 (filled circles), EP1–/– (filled triangles), EP2–/– (filled squares), EP3–/– (open circles), EP4+/+ (open triangles), and EP4–/– (open squares) mice were treated with 3% DSS for 7 days and monitored for body weight loss (a), diarrhea (b), and hemoccult (c). The numbers of mice used in this experiment were 25 (C57BL/6), 7 (EP1–/–), 10 (EP2–/–), 14 (EP3–/–), 16 (EP4–/–), and 12 (EP4+/+). (d–f) On day 7, EP4+/+ and EP4–/– mice treated with 3% DSS were sacrificed. The macroscopic examination of the large intestine is shown (d). The colon was dissected for histological analysis with H&E staining (e), and the histological injury scores were obtained (f). (g and h) Body weight loss (g) and clinical scores (h) of mice deficient in DP, FP, IP, and TP in 3% DSS colitis. DP–/–, FP+/+, FP–/–, IP–/–, and TP–/– mice were treated with 3% DSS for 7 days and monitored for body weight, diarrhea, and hemoccult. The body weight loss and clinical scores (diarrhea score plus hemoccult score) of these mice are compared with those of EP4+/+, EP4–/–, and C57BL/6 wild-type mice. The numbers of mice used in this experiment were 12 (EP4+/+), 16 (EP4–/–), 18 (C57BL/6), 11 (DP–/–), 5 (FP+/+), 4 (FP–/–), 8 (IP–/–), and 5 (TP–/–). Data in a–c and f–h are means ± SEM. *P < 0.05 versus EP4+/+ (t test) in a–c. Scale bars, 1 cm in d; 200 μm in upper and middle panel of e; 40 μm in lower panel of e.