Prostaglandin E$_{2}$ Receptors of the EP$_{2}$ and EP$_{4}$ Subtypes Regulate Activation and Differentiation of Mouse B Lymphocytes to IgE-Secreting Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 20; pp. 10978 - 10983
• Main Authors: Fedyk, Eric R., Phipps, Richard P.
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences of the United States of America 01.10.1996
• Subjects: Agonists; Antibodies; B lymphocytes; Calcium; Cultured cells; Isotypes; Messenger RNA; Prostaglandin E receptors; Prostaglandins; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.20.10978

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.