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

Biochem Biophys Res Commun. 2000 Nov 30;278(3):790-6. doi: 10.1006/bbrc.2000.3885.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Alprostadil / analogs & derivatives*
  • Alprostadil / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Blood Platelets / enzymology
  • Bucladesine / pharmacology*
  • Cells, Cultured
  • Cyclic AMP / physiology*
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dexamethasone / pharmacology
  • Dinoprostone / pharmacology*
  • Dinoprostone / physiology
  • Flurbiprofen / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Isoenzymes / blood
  • Isoenzymes / genetics*
  • Lipopolysaccharides / pharmacology*
  • Membrane Proteins
  • Monocytes / drug effects
  • Monocytes / enzymology*
  • Nitrobenzenes / pharmacology
  • Prostaglandin-Endoperoxide Synthases / blood
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology
  • Transcription, Genetic / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • Nitrobenzenes
  • RNA, Messenger
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Flurbiprofen
  • Bucladesine
  • Dexamethasone
  • Cyclic AMP
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Alprostadil
  • butaprost
  • Dinoprostone
  • 1-Methyl-3-isobutylxanthine