ANTIINFLAMMATORY EFFECT OF FK-506 ON HUMAN SKIN MAST-CELLS
ANTIINFLAMMATORY EFFECT OF FK-506 ON HUMAN SKIN MAST-CELLS
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DOI：
10.1111/1523-1747.ep12614216
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发表时间：
1992-12-01
影响因子：
6.5
通讯作者：
MARONE, G
中科院分区：
文献类型：
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作者：
DEPAULIS, A;STELLATO, C;MARONE, G
FK-506和结构上相关的大环内酯雷帕霉素是特异性结合蛋白（FK-506结合蛋白）的高亲和力配体。我们研究了FK-506和雷帕霉素对从人体皮肤组织分离的肥大细胞释放预先形成的（组胺）和从头合成的炎症介质（前列腺素D2）的影响。FK-506（0.1 - 100 nM）浓度依赖性抑制（5 - 65%）抗IgE激活的皮肤肥大细胞释放组胺。FK-506在皮肤肥大细胞中比在嗜碱性粒细胞中更有效（IC 40 = 2.15 +/- 0.78 nM vs 5.12 +/- 1.34 nM; p < 0.001），而在基底细胞中的最大抑制作用高于皮肤肥大细胞（88.77 +/- 2.44% vs 67.30 +/- 3.98%; p < 0.01）。FK-506对分别用化合物A23187和P物质攻击的皮肤肥大细胞释放组胺的抑制作用很小或没有抑制作用，而它完全抑制A23187诱导的嗜碱性粒细胞释放组胺。FK-506（0.1 - 100 nM）还可抑制（高达65%）抗IgE激发的皮肤肥大细胞中前列腺素D2的从头合成。尽管其结构相似的FK-506，雷帕霉素（10至300 nM）有很少或没有影响释放组胺从皮肤肥大细胞诱导的抗IgE，A23187，和P物质。然而，雷帕霉素竞争性拮抗FK-506的抑制作用，抗IgE诱导的组胺从皮肤肥大细胞释放的解离常数约为14 nM。这些数据表明，FK-506，而不是雷帕霉素，是一种有效的抗炎剂，作用于皮肤肥大细胞，推测是通过结合到FK-506结合蛋白。因此，似乎与FK-506结合蛋白的结合是必要的，但不足以将抑制信号传递到皮肤肥大细胞。
FK-506 and the structurally related macrolide rapamycin are high-affinity ligands for a specific binding protein (FK-506 binding protein). We examined the effects of FK-506 and rapamycin on the release of pre-formed (histamine) and de novo synthesized inflammatory mediators (prostaglandin D2) from mast cells isolated from human skin tissue. FK-506 (0.1 to 100 nM) concentration-dependently inhibited (5 to 65%) histamine release from skin mast cells activated by anti-IgE. FK-506 was more potent in skin mast cells than in basophils (IC40 = 2.15 +/- 0.78 nM versus 5.12 +/- 1.34 nM; p < 0.001), whereas the maximal inhibitory effect was higher in basoplills than in skin mast cells (88.77 +/- 2.44% versus 67.30 +/- 3.98%; p < 0.01). FK-506 had little or no inhibitory effect on histamine release from skin mast cells challenged with compound A23187 and substance P, respectively, whereas it completely suppressed A23187-induced histamine release from basophils. FK-506 (0.1 to 100 nM) also inhibited (up to 65%) the de novo synthesis of prostaglandin D2 from skin mast cells challenged with anti-IgE. Despite its structural similarity to FK-506, rapamycin (10 to 300 nM) had little or no effect on the release of histamine from skin mast cells induced by anti-IgE, A23187, and substance P. However, rapamycin competitively antagonized the inhibitory effect of FK-506 on anti-IgE-induced histamine release from skin mast cells with a dissociation constant of about 14 nM. These data indicate that FK-506, but not rapamycin, is a potent anti-inflammatory agent acting on skin mast cells presumably by binding to the FK-506 binding protein. It thus appears that binding to the FK-506 binding protein is necessary, but not sufficient, to deliver an inhibitory signal to skin mast cells.