title: FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells.
abstract: FK-506, a macrolide that binds with high affinity to a specific binding protein, and the structurally related macrolide rapamycin (RAP) were compared to cyclosporin A (CsA) for their effects on the release of preformed (histamine) and de novo synthesized (peptide leukotriene C4) inflammatory mediators from human basophils. FK-506 (1 to 300 nM) concentration dependently inhibited histamine release from basophils activated by Der p I Ag, anti-IgE, or compound A23187. FK-506 was more potent than CsA when basophils were challenged with Ag (IC50 = 25.5 +/- 9.5 vs 834.3 +/- 79.8 nM; p less than 0.001), anti-IgE (IC50 = 9.4 +/- 1.7 vs 441.3 +/- 106.7 nM; p less than 0.001), and A23187 (IC50 = 4.1 +/- 0.9 vs 36.7 +/- 3.8 nM; p less than 0.001). The maximal inhibitory effect of FK-506 was higher than that caused by CsA when basophils were activated by Der p I (80.0 +/- 3.6 vs 49.5 +/- 4.7%; p less than 0.001) and anti-IgE (90.4 +/- 1.8 vs 62.3 +/- 2.9%; p less than 0.001). FK-506 had little or no effect on the release of histamine caused by f-met peptide, phorbol myristate (12-tetradecanoyloxy-13-acetoxy-phorbol), and bryostatin 1. RAP (30 to 1000 nM) selectively inhibited only IgE-mediated histamine release from basophils, although it had no effect on mediator release caused by f-met peptide, A23187, 12-tetradecanoyloxy-13-acetoxy-phorbol, and bryostatin 1. FK-506 also inhibited the de novo synthesis of sulfidopeptide leukotriene C4 from basophils challenged with anti-IgE. Low concentrations of FK-506 and CsA synergistically inhibited the release of mediators from basophils induced by anti-IgE or compound A23187. IL-3 (3 and 10 ng/ml), but not IL-1 beta (10 and 100 ng/ml), reversed the inhibitory effect of both FK-506 and CsA on basophils challenged with anti-IgE or A23187. RAP was a competitive antagonist of the inhibitory effect of FK-506 on A23187-induced histamine release from basophils with a dissociation constant of about 30 nM. In contrast, RAP did not modify the inhibitory effect of CsA on A23187-induced histamine release. These data indicate that FK-506 is a potent antiinflammatory agent that acts on human basophils presumably by binding to a receptor site (i.e., FK-506 binding protein).
authors.affiliation: Department of Medicine, University of Naples Federico II, Italy.
authors.forename: A
authors.initials: A
authors.lastname: de Paulis
authors.forename: R
authors.initials: R
authors.lastname: Cirillo
authors.forename: A
authors.initials: A
authors.lastname: Ciccarelli
authors.forename: M
authors.initials: M
authors.lastname: Condorelli
authors.forename: G
authors.initials: G
authors.lastname: Marone
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D001491:Basophils / Q000187:drug effects*; D003524:Cyclosporins / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects*; D011090:Polyenes / Q000494:pharmacology; D011961:Receptors, Fc / Q000032:analysis; D017455:Receptors, IgE; D013189:SRS-A / Q000378:metabolism*; D020123:Sirolimus; D016559:Tacrolimus
chemical_list: D000900:Anti-Bacterial Agents; D000944:Antigens, Differentiation, B-Lymphocyte; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007377:Interleukin-3; D011090:Polyenes; D011961:Receptors, Fc; D017455:Receptors, IgE; D013189:SRS-A; D020123:Sirolimus; D016559:Tacrolimus