de Paulis A, Cirillo R, Ciccarelli A, Condorelli M, Marone G
Department of Medicine, University of Naples Federico II, Italy.
J Immunol. 1991 Apr 1;146(7):2374-81.
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).
将免疫抑制剂FK-506（一种与特定结合蛋白具有高亲和力的大环内酯类药物）及结构相关的大环内酯类药物雷帕霉素（RAP）与环孢素A（CsA）相比较，观察它们对人嗜碱性粒细胞预先形成的（组胺）和新合成的（肽白三烯C4）炎症介质释放的影响。FK-506（1至300 nM）呈浓度依赖性抑制由Der p I抗原、抗IgE或化合物A23187激活的嗜碱性粒细胞释放组胺。当嗜碱性粒细胞用抗原攻击时（半数抑制浓度[IC50] = 25.5±9.5对834.3±79.8 nM；p<0.001）、抗IgE（IC50 = 9.4±1.7对441.3±106.7 nM；p<0.001）和A23187（IC50 = 4.1±0.9对36.7±3.8 nM；p<0.001）攻击时，FK-506比CsA更有效。当嗜碱性粒细胞由Der p I（80.0±3.6对49.5±4.7%；p<0.001）和抗IgE（90.4±1.8对62.3±2.9%；p<0.001）激活时，FK-506的最大抑制作用高于CsA引起的抑制作用。FK-506对甲酰甲硫氨酸肽、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。RAP（30至1000 nM）仅选择性抑制嗜碱性粒细胞中IgE介导的组胺释放，尽管它对甲酰甲硫氨酸肽、A23187、12-十四烷酰氧基-13-乙酰氧基佛波醇和苔藓抑素1引起的介质释放没有影响。FK-506还抑制抗IgE攻击的嗜碱性粒细胞中硫肽白三烯C4的从头合成。低浓度的FK-506和CsA协同抑制抗IgE或化合物A23187诱导的嗜碱性粒细胞介质释放。白细胞介素-3（IL-3，3和10 ng/ml），而非白细胞介素-1β（IL-1β，10和100 ng/ml），可逆转FK-506和CsA对抗IgE或A23187攻击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抑制作用的竞争性拮抗剂，解离常数约为30 nM。相反，RAP不改变CsA对A23187诱导的组胺释放的抑制作用。这些数据表明，FK-506是一种强效抗炎剂，可能通过与受体位点（即FK-506结合蛋白）结合作用于人嗜碱性粒细胞。
