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前列腺素 E2-EP4 信号在实验性自身免疫性脑脊髓炎小鼠中的双重作用。

Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis.

机构信息

Departments of Pharmacology and Anesthesiology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan.

出版信息

Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12233-8. doi: 10.1073/pnas.0915112107. Epub 2010 Jun 21.

DOI:10.1073/pnas.0915112107
PMID:20566843
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2901475/
Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.

摘要

实验性自身免疫性脑脊髓炎(EAE)是多发性硬化症(MS)的动物模型。尽管 MS 患者脑脊液中的前列腺素(PG)浓度升高,但 PG 在 MS 中的作用尚不清楚。我们通过使缺乏每种 PG 受体类型或亚型的小鼠经受 EAE 诱导,并使用每种 PGE 受体(EP)亚型的激动剂或拮抗剂来研究这个问题。在缺乏 PG 受体的小鼠中,只有 EP4(-/-) 小鼠表现出 EAE 的显著抑制,这种抑制在野生型小鼠中被模拟,在 EP2(-/-) 小鼠中被 EP4 拮抗剂 ONO-AE3-208 在免疫阶段给药时更显著。在免疫阶段给予 EP4 拮抗作用也抑制了野生型小鼠中抗原特异性辅助性 T 细胞(Th)1 和 Th17 细胞的产生,在 EP2(-/-) 小鼠中更为显著。在 EAE 发病时给予 ONO-AE3-208 对疾病严重程度几乎没有影响,并且其在整个实验期间的给药并没有导致疾病峰值的显著减少,这表明除了在免疫阶段的促进作用外,EP4 在激发阶段也发挥了预防作用。在 EAE 发病时给予 EP4 激动剂 ONO-AE1-329 可延迟和抑制疾病进展,并抑制血脑屏障通透性的相关增加。因此,PGE(2) 在 EAE 中发挥双重作用,通过 EP4 和 EP2 在免疫期间冗余地促进 Th1 和 Th17 细胞的产生,并通过保护血脑屏障通过 EP4 来减轻这些细胞侵入大脑。

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