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

Acetylsalicylic acid (aspirin) is the drug most commonly selfadministered 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 kB (NF-kB). We have used interleukin 1b–induced COX-2 in human A549 cells to investigate the mechanism of action of salicylate on COX-2 activity. Sodium salicylate inhibited prostaglandin E2 release when added together with interleukin 1b for 24 hr with an IC50 value of 5 mg/ml, an effect that was independent of NF-kB 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 mM exogenous arachidonic acid. In contrast, when exogenous arachidonic acid was increased to 30 mM, sodium salicylate was a very weak inhibitor of COX-2 activity with an IC50 of .100 mg/ml. Thus, sodium salicylate is an effective inhibitor of COX-2 activity at concentrations far below those required to inhibit NF-kB (20 mg/ml) activation and is easily displaced by arachidonic acid.