Corticosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro

K. M. Skubitz, P. R. Craddock, D. E. Hammerschmidt, J. T. August

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Abstract

Inhibition of complement-mediated granulocyte aggregation has recently been proposed as a mechansim of action of high-dose corticosteroids in shock states. Postulating that such inhibition might be affected through alteration of receptor function, we examined the effect of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) on the extent and kinetics of binding of the synthetic chemotaxin f-methionine-leucine-phenylalanine (FMLP) to its specific receptor on the granulocyte surface. Dose-dependent inhibition of binding was observed at corticosteroid concentrations parralleling plasma levels achieved with 30 mg/kg intravenous bolus therapy; the order of potency was MP > HC> DEX. Receptor number was unaffected by steroid exposure, but the steroids effected a decrease in association rate constant for the FMLP-receptor interaction (35% of N for 0.2 mg/ml MP), leading to decreased receptor-ligand affinity. Dissociation kinetics, as examined by coldchase experiments, were unaltered by the corticosteroids. Furthermore, in addition to the inhibition of aggregation previously reported, aggregated granulocytes were found to disaggregate upon addition of corticosteroids; the order of potency was again MP > HC > DEX, with an MP concentration of ~2-3 mg/ml required to effect complete disaggregation. We conclude that corticosteroids can displace FMLP from the granulocyte surface by slowing association while allowing dissociation to proceed; altered kinetics of receptor-FMLP interaction may explain both the inhibition of granulocyte aggregation and granulocyte disaggregation. If these observations also hold for physiologic stimuli (such as (C5a)desarginine, which behaves similarly with respect to aggregation, inhibition, and disaggregation), such kinetic changes may be important in the clinical effects of very high-dose corticosteroids such as are administered in shock.

Original languageEnglish (US)
Pages (from-to)13-20
Number of pages8
JournalJournal of Clinical Investigation
Volume68
Issue number1
DOIs
StatePublished - 1981
Externally publishedYes

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