Cyclooxygenase inhibition in human monocytes increases endotoxin-induced TNF alpha without affecting cyclooxygenase-2 expression.
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.
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Univ.-Platz 4, A-8010 Graz, Austria.
Ruth
R
Ulcar
Bernhard A
BA
Peskar
Rufina
R
Schuligoi
Akos
A
Heinemann
Harald H
HH
Kessler
Brigitte I
BI
Santner
Rainer
R
Amann
D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases