Kabashima Kenji, Saji Tomomi, Murata Takahiko, Nagamachi Miyako, Matsuoka Toshiyuki, Segi Eri, Tsuboi Kazuhito, Sugimoto Yukihiko, Kobayashi Takuya, Miyachi Yoshiki, Ichikawa Atsushi, Narumiya Shuh
Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan.
J Clin Invest. 2002 Apr;109(7):883-93. doi: 10.1172/JCI14459.
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.
我们使用了缺乏八种前列腺素受体类型和亚型的小鼠，并研究了前列腺素在葡聚糖硫酸钠诱导（DSS诱导）的结肠炎中的作用。在前列腺素受体缺陷小鼠中，只有EP4缺陷小鼠而非DP、EP1、EP2、EP3、FP、IP或TP缺陷小鼠在接受3% DSS处理时会发生严重结肠炎，而该处理在野生型小鼠中仅诱发轻微结肠炎。通过给予EP4选择性拮抗剂（AE3 - 208），在野生型小鼠中模拟了这种表型。EP4缺陷损害了黏膜屏障功能，并导致上皮细胞丢失、隐窝损伤以及结肠中中性粒细胞和淋巴细胞聚集。相反，给野生型小鼠施用EP4选择性激动剂（AE1 - 734）可改善通常由7% DSS诱导的严重结肠炎，而AE3 - 208则抑制结肠炎的恢复并诱导CD4 + T细胞显著增殖。在体外，AE3 - 208增强而AE1 - 734抑制结肠固有层单核细胞的增殖和Th1细胞因子产生。DNA微阵列分析显示，EP4缺陷小鼠结肠中与免疫反应相关的基因表达升高，而与黏膜修复和重塑相关的基因表达降低。我们得出结论，EP4通过维持黏膜完整性和下调免疫反应来维持肠道稳态。
