Sodium Salicylate Inhibits Cyclo-Oxygenase-2 Activity Independently of Transcription Factor (Nuclear Factor κB) Activation: Role of Arachidonic Acid

• Published in: Molecular pharmacology Vol. 51; no. 6; pp. 907 - 912
• Main Authors: Mitchell, J A, Saunders, M, Barnes, P J, Newton, R, Belvisi, M G
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.1997
• Subjects: Arachidonic Acid - metabolism; Arachidonic Acid - pharmacology; Arachidonic Acid - physiology; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Enzyme Induction; Epithelial Cells; Epithelium - drug effects; Epithelium - enzymology; Humans; Interleukin-1 - pharmacology; Isoenzymes - biosynthesis; Isoenzymes - drug effects; Isoenzymes - metabolism; Lung - cytology; Lung - drug effects; Lung - enzymology; Membrane Proteins; NF-kappa B - physiology; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - drug effects; Prostaglandin-Endoperoxide Synthases - metabolism; Protein Biosynthesis - drug effects; Sodium Salicylate - pharmacology; Time Factors; Transcription, Genetic - drug effects; Transcriptional Activation - drug effects
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.51.6.907

Acetylsalicylic acid (aspirin) is the drug most commonly self-administered to reduce inflammation, swelling, and pain. The established mechanism of action of aspirin is inhibition of the enzyme cyclo-oxygenase (COX). Once taken, aspirin is rapidly deacetylated to form salicylic acid, which may account, at least in part, for the therapeutic actions of aspirin. However, where tested, salicylic acid has been found to be a relatively inactive inhibitor of COX activity in vitro , despite being an effective inhibitor of prostanoids formed at the site of inflammation in vivo . Recently, the identification of a cytokine-inducible isoform of COX, COX-2, has led to the suggestion that salicylate produces its anti-inflammatory actions by inhibiting COX-2 induction through actions on nuclear factor κB (NF-κB). We have used interleukin 1β–induced COX-2 in human A549 cells to investigate the mechanism of action of salicylate on COX-2 activity. Sodium salicylate inhibited prostaglandin E 2 release when added together with interleukin 1β for 24 hr with an IC 50 value of 5 μg/ml, an effect that was independent of NF-κB activation or COX-2 transcription or translation. Sodium salicylate acutely (30 min) also caused a concentration-dependent inhibition of COX-2 activity measured in the presence of 0, 1, or 10 μ m exogenous arachidonic acid. In contrast, when exogenous arachidonic acid was increased to 30 μ m , sodium salicylate was a very weak inhibitor of COX-2 activity with an IC 50 of >100 μg/ml. Thus, sodium salicylate is an effective inhibitor of COX-2 activity at concentrations far below those required to inhibit NF-κB (20 mg/ml) activation and is easily displaced by arachidonic acid.