Effects of ibuprofen on chemotactic peptide-receptor binding and granulocyte response

Inhibition of complement-mediated granulocyte aggregation has been proposed recently as a mechanism of action of high-dose corticosteroids and ibuprofen in shock states. Such inhibition by corticosteroids may be effected through alteration of receptor function, and we have therefore examined the effect of ibuprofen on the extent and kinetics of binding of the synthetic chemotactic peptide formylmethionine-leucine-phenylalanine (FMLP) to its specific receptor on the granulocyte surface. Dose-dependent inhibition of binding was observed at ibuprofen concentrations paralleling plasma levels achieved with 30 mg/kg intravenous bolus therapy, and also at concentrations achieved with oral therapy. Ibuprofen did not affect the receptor number, but did decrease the association rate constant for the FMLP-receptor interaction (30% of normal for 0.125 mg/ml ibuprofen), leading to a decrease in receptor affinity for ligand. Dissociation kinetics, as determined by cold chase experiments, were unaltered by ibuprofen. We conclude that ibuprofen, like corticosteroids, can slow the rate of association of FMLP with its receptor on the granulocyte surface while allowing dissociation to proceed; altered kinetics of receptor-FMLP interaction may explain the inhibition of granulocyte aggregation. Blockade of granulocyte surface receptors for inflammatory stimuli may be important in the clinical effects of very high-dose corticosteroids and ibuprofen such as are administered in shock; such effects are seen at blood levels of ibuprofen that occur with oral therapy. Similar observations may hold for other physiologic stimuli.