Prostaglandin E(2) receptors of the EP(2) and EP(4) subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells
Prostaglandin E(2) receptors of the EP(2) and EP(4) subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells
复制标题
DOI：
10.1073/pnas.93.20.10978
复制
发表时间：
1996-10-01
影响因子：
11.1
通讯作者：
Phipps, RP
中科院分区：
文献类型：
--
作者：
Fedyk, ER;Phipps, RP
前列腺素E（2）（PGE（2））是一种有效的脂质分子，具有复杂的促炎和免疫调节特性。PGE（2）可以通过刺激B淋巴细胞产生IgE抗体和辅助性T细胞2型细胞因子的合成来塑造免疫应答[例如，白细胞介素（IL）-4，IL-10]，同时抑制Th 1细胞因子（例如，干扰素-γ，IL-12）。目前还不清楚什么类型的受体结合PGE（2）并调节这些反应。最近在非造血细胞中的分析已经鉴定出六种PGE（2）受体（EP（1）、EP（2）、EP（3 α）、EP（3 β）、EP（3 γ）和EP（4））。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EP（1）、EP（2）、EP（3 β）和EP（4）受体的mRNA。使用优先结合EP受体亚型的小分子激动剂研究每种受体的免疫调节功能。与EP（1）和EP（3）激动剂不同，结合EP（2）或EP（2）和EP（4）受体的激动剂强烈抑制II类主要组织相容性复合物和CD 23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。PGE（2）促进分化并协同增强IL-4和脂多糖驱动的B细胞免疫球蛋白类向IgE的转换。结合EP（2）或EP（2）和EP（4）受体的激动剂也强烈刺激向IgE的类别转换。使用cAMP代谢抑制剂的实验表明，EP（2）和EP（4）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，EP（2）和EP（4）受体的拮抗剂对于减少过敏和IgE介导的哮喘反应将是重要的。
Prostaglandin E(2) (PGE(2)) is a potent lipid molecule with complex proinflammatory and immunoregulatory properties. PGE(2) 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 PGE(2) and modulates these responses. Recent analyses in nonhematopoietic cells have identified six PGE(2) receptors (EP(1), EP(2), EP(3 alpha), EP(3 beta), EP(3 gamma), and EP(4)). This investigation examines quiescent B lymphocytes and reports that these cells express mRNA encoding EP(1), EP(2), EP(3 beta), and EP(4) receptors. The immunoregulatory functions of each receptor were investigated using small molecule agonists that preferentially bind EP receptor subtypes. Unlike agonists for EP(1) and EP(3), agonists that bound EP(2) or EP(2) and EP(4) 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. PGE(2) promotes differentiation and synergistically enhances IL-4 and lipopolysaccharide-driven B-cell immunoglobulin class switching to IgE. Agonists that bound EP(2) or EP(2) and EP(4) receptors also strongly stimulated class switching to IgE. Experiments employing inhibitors of cAMP metabolism demonstrate that the mechanism by which EP(2) and EP(4) receptors regulate B lymphocyte activity requires elevation of cAMP. In conclusion, these data suggest that antagonists to EP(2) and EP(4) receptors will be important for diminishing allergic and IgE-mediated asthmatic responses.