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标题：Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis
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作者：Yoshiyasu Esaki ; Youxian Li ; Daiji Sakata 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：27
页码：12233-12238
DOI：10.1073/pnas.0915112107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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, PGE2 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.
关键词：disease model ; knockout mice ; prostaglandin ; prostaglandin receptor ; multiple sclerosis