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

K Brune, B Hinz, A Pahl

Journal: Biochemical and biophysical research communications 2001;278(3):790-6

PMID: 11095985

Full Text on Elsevier Science View on PubMed

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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2), butaprost (selective agonist of the adenylyl cyclase-coupled EP(2) receptor) and 11-deoxy PGE(1) (EP(2)/EP(4) agonist), whereas sulprostone (EP(3)/EP(1) agonist) left COX-2 expression unaltered. Abrogation of LPS-induced PGE(2) synthesis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mRNA levels that was restored by exogenous PGE(2) and mimicked by S(+)-flurbiprofen 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 monocytes via a positive feedback mechanism.

Address: Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, D-91054, Germany. [email protected]

DOI: 10.1006/bbrc.2000.3885

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MeSH Terms: 1-Methyl-3-isobutylxanthine, Alprostadil, Anti-Inflammatory Agents, Non-Steroidal, Blood Platelets, Bucladesine, Cells, Cultured, Cyclic AMP, Cyclooxygenase 1, Cyclooxygenase 2, Dexamethasone, Dinoprostone, Flurbiprofen, Gene Expression Regulation, Enzymologic, Humans, Isoenzymes, Lipopolysaccharides, Membrane Proteins, Monocytes, Nitrobenzenes, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides, Transcription, Genetic