FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells.
FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells.
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FK-506 是一种有效的新型抑制剂，可抑制人 Fc epsilon RI 细胞释放促炎介质。
作者：
A. Paulis;R. Cirillo;A. Ciccarelli;Mario Condorelli;Gianni Marone
FK-506是一种与特异性结合蛋白具有高亲和力结合的大环内酯类药物，结构上相关的大环内酯类药物雷帕霉素（RAP）与环孢菌素A（CsA）对人嗜碱性粒细胞释放预先形成的（组胺）和从头合成的（肽白三烯C4）炎症介质的影响进行了比较。FK-506（1至300 nM）浓度依赖性地抑制组胺从Der p I Ag、抗IgE或化合物A23187激活的嗜碱性粒细胞释放。FK-506对嗜碱性粒细胞的杀伤作用强于CsA（IC 50 = 25.5 +/- 9.5 vs 834.3 +/- 79.8 nM; p小于0.001），抗IgE（IC 50 = 9.4 +/- 1.7 vs 441.3 +/- 106.7 nM; p小于0.001）和A23187（IC 50 = 4.1 +/- 0.9 vs 36.7 +/- 3.8 nM; p小于0.001）。当嗜碱性粒细胞被Der p I（80.0 +/- 3.6 vs 49.5 +/- 4.7%; p <0.001）和抗IgE（90.4 +/- 1.8 vs 62.3 +/- 2.9%; p <0.001）激活时，FK-506的最大抑制作用高于CsA引起的最大抑制作用。FK-506对由f-met肽、佛波醇肉豆蔻酸酯（12-十四烷酰氧基-13-乙酰氧基-佛波醇）和苔藓抑素1引起的组胺释放几乎没有影响或没有影响。RAP（30至1000 nM）选择性抑制IgE介导的组胺释放嗜碱性粒细胞，虽然它没有影响介质释放引起的f-met肽，A23187，12-十四烷酰氧基-13-乙酰氧基-佛波醇，苔藓抑素1。FK-506还抑制用抗IgE激发的嗜碱性粒细胞的硫肽白三烯C4的从头合成。低浓度的FK-506和CsA协同抑制由抗IgE或化合物A23187诱导的介质从嗜碱性粒细胞的释放。IL-3（3和10 ng/ml），而不是IL-1 β（10和100 ng/ml），逆转FK-506和CsA对抗IgE或A23187激发的嗜碱性粒细胞的抑制作用。RAP是FK-506对A23187诱导的嗜碱性粒细胞组胺释放的抑制作用的竞争性拮抗剂，解离常数约为30 nM。与此相反，RAP没有修改CsA对A23187诱导的组胺释放的抑制作用。这些数据表明，FK-506是一种有效的抗肿瘤剂，其可能通过结合受体位点（即，FK-506结合蛋白）。
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).