Cyclooxygenase inhibition in human monocytes increases endotoxin-induced TNF alpha without affecting cyclooxygenase-2...

Human endotoxin-stimulated adherent monocytes were used in order to determine whether or not NSAIDs influence cyclooxygenase-2 and/or tumor necrosis factor (TNF)alpha expression within the range of inhibitor concentrations that are required to suppress prostaglandin biosynthesis. Exogenous prostaglandin E(2) (IC(50)<5 nM) inhibited endotoxin-induced TNFalpha mRNA and protein while, up to 1 microM, it did not significantly affect cyclooxygenase-2 mRNA expression. Similar results were obtained using the membrane-permeable cAMP analogue db-cAMP, which caused preferential inhibition of TNFalpha expression. Indomethacin or lysine-acetylsalicylic acid concentration-dependently inhibited prostaglandin E(2) biosynthesis and, at concentrations causing near-complete inhibition, enhanced TNFalpha mRNA and protein expression without significantly influencing cyclooxygenase-2 mRNA. In addition, by facilitating endotoxin-induced TNFalpha expression, indomethacin or lysine-acetylsalicylic acid counteracted dexamethasone-induced inhibition of TNFalpha biosynthesis, thereby exhibiting an effect opposite to that of exogenous prostaglandin E(2). The results suggest that in human endotoxin-stimulated monocytes, NSAIDs can enhance TNFalpha expression through inhibition of cyclooxygenase and the resulting decrease in prostanoid biosynthesis.