Corticosteroids reversibly inhibit chemotactic peptide-receptor binding and granulocyte response, yet allow desensitization and receptor down-regulation.
Inhibition of complement-mediated granulocyte aggregation has recently been proposed as a mechanism of action of high-dose corticosteroids in shock states. Such inhibition may be effected through alteration of receptor function. Methylprednisolone inhibits binding of the synthetic chemotaxin f-methionine-leucine-phenylalanine (FMLP) to its surface receptor on granulocytes in a dose-dependent manner by slowing the association rate of the FMLP-receptor interaction without altering receptor number. Because the half-life of high-dose methylprednisolone in vivo is short, we examined the reversibility of its effects on granulocyte aggregation and receptor function; both effects were readily reversed by washing. Furthermore, methylprednisolone, at concentrations that profoundly inhibited the granulocyte aggregation response to FMLP, allowed the occurrence of FMLP-receptor down-regulation and granulocyte desensitization to further stimulation by FMLP. We conclude that methylprednisolone at concentrations that inhibit granulocyte aggregation can slow the rate of the FMLP-receptor interaction while simultaneously allowing receptor down-regulation and granulocyte desensitization to proceed. Transient blockade of granulocyte function with concomitant desensitization and receptor down-regulation may be important in the clinical effects of very high-dose corticosteroids such as are administered in shock and could partially explain how drugs with such short half-lives administered intermittently could exert a beneficial effect in shock states. Similar observations may hold for other physiologic stimuli.
D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008775:Methylprednisolone / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism*
D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D009240:N-Formylmethionine Leucyl-Phenylalanine; D008775:Methylprednisolone