Fedyk E R, Phipps R P
Department of Microbiology, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10978-83. doi: 10.1073/pnas.93.20.10978.
Prostaglandin E2 (PGE2) is a potent lipid molecule with complex proinflammatory and immunoregulatory properties. PGE2 can shape the immune response by stimulating the production of IgE antibody by B lymphocytes and the synthesis of T-helper type 2 cytokines [e.g., interleukin (IL)-4, IL-10], while inhibiting production of Th1 cytokines (e.g., interferon-gamma, IL-12). It is unknown what type of receptor binds PGE2 and modulates these responses. Recent analyses in nonhematopoietic cells have identified six PGE2 receptors (EP1, EP2, EP3 alpha, EP3 beta, EP3 gamma, and EP4). This investigation examines quiescent B lymphocytes and reports that these cells express mRNA encoding EP1, EP2, EP3 beta, and EP4 receptors. The immunoregulatory functions of each receptor were investigated using small molecule agonists that preferentially bind EP receptor subtypes. Unlike agonists for EP1 and EP3, agonists that bound EP2 or EP2 and EP4 receptors strongly inhibited expression of class II major histocompatibility complex and CD23 and blocked enlargement of mouse B lymphocytes stimulated with IL-4 and/or lipopolysaccharide. PGE2 promotes differentiation and synergistically enhances IL-4 and lipopolysaccharide-driven B-cell immunoglobulin class switching to IgE. Agonists that bound EP2 or EP2 and EP4 receptors also strongly stimulated class switching to IgE. Experiments employing inhibitors of cAMP metabolism demonstrate that the mechanism by which EP2 and EP4 receptors regulate B lymphocyte activity requires elevation of cAMP. In conclusion, these data suggest that antagonists to EP2 and EP4 receptors will be important for diminishing allergic and IgE-mediated asthmatic responses.
前列腺素E2（PGE2）是一种具有复杂促炎和免疫调节特性的强效脂质分子。PGE2可通过刺激B淋巴细胞产生IgE抗体以及合成2型辅助性T细胞细胞因子[如白细胞介素（IL）-4、IL-10]来塑造免疫反应，同时抑制Th1细胞因子（如干扰素-γ、IL-12）的产生。尚不清楚哪种类型的受体与PGE2结合并调节这些反应。最近对非造血细胞的分析已鉴定出六种PGE2受体（EP1、EP2、EP3α、EP3β、EP3γ和EP4）。本研究检测了静止的B淋巴细胞，并报告这些细胞表达编码EP1、EP2、EP3β和EP4受体的mRNA。使用优先结合EP受体亚型的小分子激动剂研究了每种受体的免疫调节功能。与EP1和EP3的激动剂不同，结合EP2或EP2和EP4受体的激动剂强烈抑制II类主要组织相容性复合体和CD23的表达，并阻断IL-4和/或脂多糖刺激的小鼠B淋巴细胞的扩增。PGE2促进分化，并协同增强IL-4和脂多糖驱动的B细胞免疫球蛋白类别转换为IgE。结合EP2或EP2和EP4受体的激动剂也强烈刺激类别转换为IgE。采用cAMP代谢抑制剂的实验表明，EP2和EP4受体调节B淋巴细胞活性的机制需要cAMP升高。总之，这些数据表明，EP2和EP4受体的拮抗剂对于减轻过敏和IgE介导的哮喘反应将具有重要意义。
