Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice

Abstract

PGE2 has been known to suppress Th1 responses. We studied the difference in strains of mice in PGE2 production by macrophages and its relation to Th1 activation. Macrophages from BALB/c mice produced greater amounts of PGE2 than those from any other strains of mice, including C57BL/6, after LPS stimulation. In accordance with the amount of PGE2 produced, macrophage-derived IL-12 and T cell-derived IFN-γ production were more strongly suppressed in BALB/c macrophages than in C57BL/6 macrophages. When macrophages were treated with indomethacin or EP4 antagonist, Th1 cytokines were more markedly increased in cells from BALB/c mice than in those from C57BL/6 mice. Although cyclooxygenase-2 was expressed similarly after LPS stimulation in these mouse strains, the release of arachidonic acid and the expression of type V secretory phospholipase A2 mRNA were greater in BALB/c macrophages. However, exogenous addition of arachidonic acid did not reverse the lower production of PGE2 by C57BL/6 macrophages. The expression of microsomal PGE synthase, a final enzyme of PGE2 synthesis, was also greater in BALB/c macrophages. These results indicate that the greater production of PGE2 by macrophages, which is regulated by secretory phospholipase A2 and microsomal PGE synthase but not by cyclooxygenase-2, is related to the suppression of Th1 cytokine production in BALB/c mice.