Prostaglandin E2 increases the expression of cyclooxygenase-2 in cultured rat microglia.

Prostaglandin E-2 (PGE(2)) plays pivotal roles in controlling microglial activation with the EP2 receptor, a PGE(2) receptor subtype. Activated microglia are often reported to increase cyclooxygenase (COX)-2 expression, followed by PGE(2) production, but it is unclear whether extracellular PGE(2) is involved in microglial PGE(2) synthesis. In the present study, we report that PGE(2) increases COX-2 protein in microglia. In a culture system, PGE(2) at 10(-6) M for 3 h increased COX-2 and microsomal PGE synthase (mPGES)-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cytosolic PGE synthase (cPGES) in microglia. PGE(2) at 10(-6) M for 3 h also increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. An EP2 agonist, ONO-AE1-259-01, also increased COX-2 and mPGES-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cPGES, whereas an EP1 agonist, ONO-DI-004, an EP3 agonist, ONO-AE-248, and an EP4 agonist, ONO-AE1-329, had no effect. Similar to PGE(2), ONO-AE1-259-01 increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. In addition, the effects of PGE(2) were inhibited by an EP2 antagonist, PF-04418948, but not by an EP1 antagonist, ONO-8713, an EP3 antagonist, ONO-AE3-240, or an EP4 antagonist, ONO-AE3-208, at 10(-6) M. On the other hand, lipopolysaccharide (LPS) increased PGE(2) production, but the LPS-induced PGE(2) production was not affected by ONO-8713, PF-04418948, ONO-AE3-240, or ONO-AE3-208. These results indicate that PGE(2) increases COX-2 protein in microglia through the EP2 receptor supporting the idea that extracellular PGE(2) has a triggering aspect for microglial activation.