Prostaglandin E2-EP3 signaling suppresses skin inflammation in murine contact hypersensitivity
Prostaglandin E2-EP3 signaling suppresses skin inflammation in murine contact hypersensitivity
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DOI：
10.1016/j.jaci.2009.04.029
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发表时间：
2009-10-01
影响因子：
14.2
通讯作者：
Narumiya, Shuh
中科院分区：
文献类型：
--
作者：
Honda, Tetsuya;Matsuoka, Toshiyuki;Narumiya, Shuh
背景：前列腺素E-2通过4种G蛋白偶联受体EP 1、EP 2、EP 3和EP 4发挥多种作用。我们已经报道了PGE（2）作用于气道上皮细胞中的EP 3，并在卵白蛋白诱导的小鼠过敏性哮喘中发挥抗炎作用。虽然EP 3也在皮肤中表达，并且在皮肤变应性炎症过程中大量产生PGE（2），但PGE（2）-EP 3信号在皮肤变应性炎症中的作用仍不清楚。目的：我们试图研究PGE（2）-EP 3信号在皮肤变应性炎症中是否发挥抗炎作用。我们使用鼠接触性超敏反应（CHS）模型，并通过使用EP 3选择性激动剂ONO-AE-248（AE 248）和EP 3缺陷小鼠来检查EP 3的作用。通过半抗原激发的耳的厚度和组织学来评价炎症。炎症相关的基因表达变化和AE 248的影响通过皮肤微阵列分析进行了检查。通过对EP 3缺陷小鼠中EP 3基因座处敲入的β-半乳糖苷酶进行染色来检查EP 3的定位。EP 3的行动也在培养的角质形成cytokes.Results：AE 248在诱导阶段的管理显着抑制CHS相比，在车辆处理的小鼠。微阵列分析显示，给予AE 248抑制了激发位点的趋化因子（包括CXCL 1）的基因表达。在EP 3缺陷小鼠中的X-gal染色揭示了在角质形成细胞中的EP 3表达，这在野生型小鼠中通过抗EP 3抗体进一步证实。结论：PGE（2）-EP 3信号通路抑制角质形成细胞的活化并发挥抗炎作用。（J Allergy Clin Immunol 2009;124：809-18.）
Background: Prostaglandin (PG) E-2 exerts a variety of actions through 4 G protein-coupled receptors designated as EP1, EP2, EP3, and EP4. We have reported that PGE(2) acts on EP3 in airway epithelial cells and exerts anti-inflammatory actions in ovalbumin-induced murine allergic asthma. Although EP3 is also expressed in skin and PGE(2) is produced abundantly during skin allergic inflammation, the role of PGE(2)-EP3 signaling in skin allergic inflammation remains unknown.Objective: We sought to investigate whether PGE(2)-EP3 signaling exerts anti-inflammatory actions in skin allergic inflammation.Methods: We used a murine contact hypersensitivity (CHS) model and examined the role of EP3 by using an EP3-selective agonist, ONO-AE-248 (AE248), and EP3-deficient mice. The inflammation was evaluated by the thickness and histology of the hapten-challenged ear. Inflammation-associated changes in gene expression and effects of AE248 were examined by means of microarray analysis of the skin. Localization of EP3 was examined by staining for beta-galactosidase knocked in at the EP3 locus in EP3-deficient mice. EP3 action was also examined in cultured keratinocytes.Results: Administration of AE248 during the elicitation phase significantly suppressed CHS compared with that seen in vehicle-treated mice. Microarray analysis revealed that administration of AE248 inhibited the gene expression of neutrophil-recruiting chemokines, including CXCL1, at the elicitation site. X-gal staining in EP3-deficient mice revealed EP3 expression in keratinocytes, which was further confirmed by anti-EP3 antibody in wild-type mice. In cultured keratinocytes AE248 suppressed CXCL1 production induced by TNF-alpha.Conclusion: PGE(2)-EP3, signaling inhibits keratinocytes activation and exerts anti-inflammatory actions in murine CHS. (J Allergy Clin Immunol 2009;124:809-18.)