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 4

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Impaired mucosal integrity caused by the EP4-deficiency. (a) Effect of t...
Impaired mucosal integrity caused by the EP4-deficiency. (a) Effect of the EP4 antagonist. C57BL/6 mice were treated with either vehicle (None), 3% DSS alone, AE3-208 (EP4 antagonist) alone, or 3% DSS and AE3-208 in combination for 1 day. FITC-dextran was administered by mouth, and the serum level was measured 4 hours later. Data are means ± SEM from six mice per group. *P < 0.05 versus the vehicle-treated mice (t test). (b) DSS-induced submucosal infiltration of FITC-dextran in EP4-deficient mice. FITC-dextran was administered by mouth to EP4+/+ and EP4–/– mice pretreated with 3% DSS for 1 day. Four hours later the colon was excised and subjected to fluorescent microscopic examination. Scale bars, 1 mm.