Cyclooxygenase-2 expression in lipopolysaccharide-stimulated human monocytes is modulated by cyclic AMP, prostaglandin E-2, and nonsteroidal anti-inflammatory drugs

Using human blood monocytes (for determination of cyclooxygenase-2 (COX-2) mRNA by RT-PCR) and human whole blood (for prostanoid determination), the p resent study investigates the influence of the second messenger cAMP on Lip opolysaccharide (LPS)-induced COX-2 expression with particular emphasis on the role of prostaglandin E-2 (PGE(2)) in this process. Elevation of intrac ellular cAMP with a cell-permeable cAMP analogue (dibutyryl cAMP), an adeny lyl cyclase activator (cholera toxin), or a phosphodiesterase inhibitor (3- isobutyl-1-methylxanthine) substantially enhanced LPS-induced PGE(2) format ion and COX-2 mRNA expression, but did not modify COX-2 enzyme activity. Mo reover, up-regulation of LPS-induced COX-2 expression was caused by PGE(2), butaprost (selective agonist of the adenylyl cyclase-coupled EP2 receptor) and Il-deoxy PGE(1) (EP2/EP4 agonist), whereas sulprostone (EP3/EP1 agonis t) left COX-2 expression unaltered. Abrogation of LPS-induced PGE(2) synthe sis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mR NA levels that was restored by exogenous PGE(2) and mimicked by S(S)-flurbi profen and ketoprofen. Overall, these results indicate a modulatory role of cAMP in the regulation of COX-2 expression. PGE(2), a cAMP-elevating final product of the COX-2 pathway, may autoregulate COX-2 expression in human m onocytes via a positive feedback mechanism. (C) 2000 Academic Press.