TY - JOUR
T1 - Corticosteroids reversibly inhibit chemotactic peptide-receptor binding and granulocyte response, yet allow desensitization and receptor down-regulation
AU - Skubitz, K. M.
AU - Hammerschmidt, D. E.
PY - 1986
Y1 - 1986
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.v68.4.830.bloodjournal684830
DO - 10.1182/blood.v68.4.830.bloodjournal684830
M3 - Article
C2 - 3756350
AN - SCOPUS:0022969305
SN - 0006-4971
VL - 68
SP - 830
EP - 836
JO - Blood
JF - Blood
IS - 4
ER -