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) (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.