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

Prostaglandin E₂ (PGE₂) plays pivotal roles in controlling microglial activation with the EP₂ receptor, a PGE₂ receptor subtype. Activated microglia are often reported to increase cyclooxygenase (COX)-2 expression, followed by PGE₂ production, but it is unclear whether extracellular PGE₂ is involved in microglial PGE₂ synthesis. In the present study, we report that PGE₂ increases COX-2 protein in microglia. In a culture system, PGE₂ 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. PGE₂ 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 PGE₂, 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 PGE₂ 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 PGE₂ production, but the LPS-induced PGE₂ production was not affected by ONO-8713, PF-04418948, ONO-AE3-240, or ONO-AE3-208. These results indicate that PGE₂ increases COX-2 protein in microglia through the EP₂ receptor supporting the idea that extracellular PGE₂ has a triggering aspect for microglial activation.