FK-506 and cyclosporin A: selective inhibition of calcium ionophore-induced polymorphonuclear leukocyte degranulation.
This paper investigates the abilities of FK-506 and cyclosporin A (CsA) to inhibit human polymorphonuclear leukocyte (PMNL) degranulation. PMNLs, purified from human blood, were stimulated in vitro with A23187, ionomycin, the complement derived peptide C5a, formylmethionylleucinylphenylalanine (FMLP) or phorbol myristate acetate (PMA). Degranulation was assessed by measuring the release of either lactoferrin or N-acetyl-beta-D-glucosaminidase (NAG). Both FK-506 and CsA produced a concentration-related inhibition of degranulation induced by either A23187 or ionomycin but did not affect C5a-, FMLP- or PMA-induced degranulation. The IC50 values for inhibition of degranulation (approximately 0.7 nM for FK-506 and 33.7 nM for CsA) are very close to the published values for inhibition of human T-cell proliferation. Removal of calcium from the incubation medium with ethyleneglycolbis(aminoethylether)tetra-acetate (EGTA) totally inhibited calcium ionophore-induced degranulation but had no effect against C5a-, FMLP- or PMA-induced degranulation. Preincubation of PMNLs with actinomycin D or cycloheximide did not affect either A23187- or PMA-induced degranulation. Non-immunosuppressive analogs of CsA were ineffective at inhibiting degranulation. Rapamycin, a macrolide structurally related to FK-506, did not inhibit degranulation but it did antagonize the inhibition produced by FK-506. Given the similar profiles of activity of FK-506 and CsA in neutrophils and T cells, we conclude that similar activation or signal transduction pathways may be present in both T cells and neutrophils. Because A23187-induced PMNL degranulation was not sensitive to either actinomycin D or cycloheximide, it is apparent that the signal transduction pathways ultimately control different cellular functions.
Forrest
M J
MJ
Department of Immunology Research, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
Jewell
M E
ME
Koo
G C
GC
Sigal
N H
NH
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D015759:Ionomycin / Q000494:pharmacology; D007781:Lactoferrin / Q000032:analysis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011090:Polyenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D016559:Tacrolimus; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D003524:Cyclosporins; D011090:Polyenes; D003609:Dactinomycin; D000001:Calcimycin; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003513:Cycloheximide; D007781:Lactoferrin; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus; D016559:Tacrolimus