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

Prostaglandin E ₂ (PGE ₂ ) plays pivotal roles in controlling microglial activation with the EP ₂ 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 EP ₂ 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 EP ₁ agonist, ONO-DI-004, an EP ₃ agonist, ONO-AE-248, and an EP ₄ 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 EP ₂ antagonist, PF-04418948, but not by an EP ₁ antagonist, ONO-8713, an EP ₃ antagonist, ONO-AE3-240, or an EP ₄ 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 EP ₂ receptor supporting the idea that extracellular PGE ₂ has a triggering aspect for microglial activation.
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