PGE 2 has been known to suppress Th1 responses. We studied the difference in strains of mice in PGE 2 production by macrophages and its relation to Th1 activation. Macrophages from BALB/c mice produced greater amounts of PGE 2 than those from any other strains of mice, including C57BL/6, after LPS stimulation. In accordance with the amount of PGE 2 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 A 2 mRNA were greater in BALB/c macrophages. However, exogenous addition of arachidonic acid did not reverse the lower production of PGE 2 by C57BL/6 macrophages. The expression of microsomal PGE synthase, a final enzyme of PGE 2 synthesis, was also greater in BALB/c macrophages. These results indicate that the greater production of PGE 2 by macrophages, which is regulated by secretory phospholipase A 2 and microsomal PGE synthase but not by cyclooxygenase-2, is related to the suppression of Th1 cytokine production in BALB/c mice.