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Prostaglandin E2 Upregulates Cyclooxygenase-2 Expression in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

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Abstract

Prostaglandin E2 (PGE2) has been implicated in the regulation of inflammatory and immunological events. Using RAW 264.7 macrophages, the present study investigates the influence of PGE2 on the expression of cyclooxygenase-2 (COX-2). Incubation of cells with PGE2 increased lipopolysaccharide (LPS)-induced COX-2 mRNA levels in a concentration-dependent manner. Upregulation of COX-2 expression by PGE2 was completely abolished by the specific adenylyl cyclase inhibitor 2′,5′-dideoxyadenosine and mimicked by butaprost, a selective agonist of the adenylyl cyclase-coupled PGE2 receptor subtype 2 (EP2), or 11-deoxy PGE1, an EP2/EP4 receptor agonist. By contrast, the EP3/EP1 receptor agonists 17-phenyl-ω-trinor PGE2 and sulprostone left LPS-induced COX-2 expression virtually unaltered. Upregulation of LPS-induced COX-2 expression and subsequent PGE2 synthesis was also observed in the presence of the cell-permeable cAMP analogue dibutyryl cAMP and the adenylyl cyclase activator cholera toxin. Together, our data demonstrate that PGE2 potentiates COX-2 mRNA expression via an adenylyl cyclase/cAMP-dependent pathway. In conclusion, upregulation of COX-2 expression via an autocrine feed-forward loop may in part contribute to the well-known capacity of PGE2/cAMP to modulate inflammatory processes.

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    Abbreviations used: COX-2, cyclooxygenase-2; CRE, cAMP-response element; cAMP, cyclic adenosine monophosphate; dbcAMP; dibutyryl cAMP; IL, interleukin; LPS, lipopolysaccharide; NO, nitric oxide; PG, prostaglandin; TNF, tumor necrosis factor.

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