The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
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DOI：
10.1172/jci200214459
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发表时间：
2002-04-01
影响因子：
15.9
通讯作者：
Narumiya, S
中科院分区：
文献类型：
--
作者：
Kabashima, K;Saji, T;Narumiya, S
我们使用了八种前列腺素受体类型和亚型中每一种都缺乏的小鼠，并研究了前列腺素在葡聚糖硫酸钠诱导(DSS诱导)结肠炎中的作用。在前列腺素受体缺陷小鼠中，只有EP4缺陷小鼠和DP、EP1、EP2、EP3、FP、IP或TP缺乏的小鼠在3%DSS治疗下发生严重结肠炎，仅在野生型小鼠中诱导边缘结肠炎。这一表型在野生型小鼠中通过给予EN选择性拮抗剂(AE3-208)来模拟。EN缺乏损害了粘膜屏障功能，并导致结肠上皮细胞丢失、隐窝损伤以及中性粒细胞和淋巴细胞聚集。相反，给野生型小鼠注射EP4选择性激动剂(AE1-734)可以改善通常由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促进结肠固有层单核细胞的增殖，AE1-734抑制Th1细胞因子的产生。DNA微阵列分析显示，Ep4基因缺陷小鼠结肠中与免疫反应相关的基因表达增加，而与粘膜修复和重塑相关的基因表达降低。我们的结论是，EP4通过保持粘膜完整性和下调免疫反应来维持肠道的动态平衡。
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 EN-selective antagonist (AE3-208). The EN 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.