Cyclooxygenase-2 Expression in Lipopolysaccharide-Stimulated Human Monocytes Is Modulated by Cyclic AMP, Prostaglandin E2, and Nonsteroidal Anti-inflammatory Drugs

Abstract

Using human blood monocytes (for determination of cyclooxygenase-2 (COX-2) mRNA by RT-PCR) and human whole blood (for prostanoid determination), the present study investigates the influence of the second messenger cAMP on lipopolysaccharide (LPS)-induced COX-2 expression with particular emphasis on the role of prostaglandin E2 (PGE2) in this process. Elevation of intracellular cAMP with a cell-permeable cAMP analogue (dibutyryl cAMP), an adenylyl cyclase activator (cholera toxin), or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) substantially enhanced LPS-induced PGE2 formation and COX-2 mRNA expression, but did not modify COX-2 enzyme activity. Moreover, up-regulation of LPS-induced COX-2 expression was caused by PGE2, butaprost (selective agonist of the adenylyl cyclase-coupled EP2 receptor) and 11-deoxy PGE1 (EP2/EP4 agonist), whereas sulprostone (EP3/EP1 agonist) left COX-2 expression unaltered. Abrogation of LPS-induced PGE2 synthesis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mRNA levels that was restored by exogenous PGE2 and mimicked by S(+)-flurbiprofen and ketoprofen. Overall, these results indicate a modulatory role of cAMP in the regulation of COX-2 expression. PGE2, a cAMP-elevating final product of the COX-2 pathway, may autoregulate COX-2 expression in human monocytes via a positive feedback mechanism.