The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
Kenji Kabashima, … , Atsushi Ichikawa, Shuh Narumiya
Kenji Kabashima, … , Atsushi Ichikawa, Shuh Narumiya
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):883-893. https://doi.org/10.1172/JCI14459.
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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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Figure 1

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Induction of colitis by indomethacin in mice treated with 3% DSS and sup...
Induction of colitis by indomethacin in mice treated with 3% DSS and suppression of this effect by dm-PGE2. (a–c) Wild-type C57BL/6 mice were treated with either 3% DSS alone (diamonds), 3% DSS and indomethacin (squares), or 3% DSS, indomethacin, and dm-PGE2 (triangles), and monitored for body weight loss (a), diarrhea (b), and hemoccult (c) for 7 days. (d and e) On day 7, the mice were sacrificed. The colon was dissected for histological analysis with H&E staining (e), and the histological injury scores were obtained (d). Blood was collected for measurement of the WBC number (f) and HCT (g). The weights of spleens of the sacrificed animals are shown (h). N, mice treated with vehicle; D, mice treated with 3% DSS alone; D+I, mice treated with 3% DSS and indomethacin; D+I+E, mice treated with 3% DSS, indomethacin, and dm-PGE2. Data in a–d and f–h are means ± SEM from six animals. *P < 0.05 versus D (Dunnett). #P < 0.05 versus D+I (Dunnett multiple comparison test). Scale bars, 200 μm in e.