부산대학교 도서관

Prostaglandin [E.sub.2] (PG[E.sub.2]) is a potent lipid molecule with complex proinflammatory and immunoregulatory properties. PG[E.sub.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 PG[E.sub.2] and modulates these responses. Recent analyses in nonhematopoietic cells have identified six PG[E.sub.2] receptors (E[P.sub.1], E[P.sub.2], E[P.sub.3[Alpha]], E[P.sub.3[Beta]], E[P.sub.3[Gamma]], and E[P.sub.4]). This investigation examines quiescent B lymphocytes and reports that these cells express mRNA encoding E[P.sub.1], E[P.sub.2], E[P3.sub.[Beta]], and E[P.sub.4] receptors. The immunoregulatory functions of each receptor were investigated using small molecule agonists that preferentially bind EP receptor subtypes. Unlike agonists for E[P.sub.1] and E[P.sub.3], agonists that bound E[P.sub.2] or E[P.sub.2] and E[P.sub.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. PG[E.sub.2] promotes differentiation and synergistically enhances IL-4 and lipopolysaccharide-driven B-cell immunoglobulin class switching to IgE. Agonists that bound E[P.sub.2] or E[P.sub.2] and E[P.sub.4] receptors also strongly stimulated class switching to IgE. Experiments employing inhibitors of cAMP metabolism demonstrate that the mechanism by which E[P.sub.2] and E[P.sub.4] receptors regulate B lymphocyte activity requires elevation of cAMP. In conclusion, these data suggest that antagonists to E[P.sub.2] and E[P.sub.4] receptors will be important for diminishing allergic and IgE-mediated asthmatic responses.