Hultsch T, Albers M W, Schreiber S L, Hohman R J
Allergic Diseases Section, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6229-33. doi: 10.1073/pnas.88.14.6229.
Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism.
对免疫亲和素配体FK506、环孢菌素A（CsA）、雷帕霉素和506BD的作用及相互作用的研究表明，FK506与FK506结合蛋白的复合物或CsA与亲环蛋白（CsA结合蛋白）的复合物会抑制T细胞受体介导的信号转导，该信号转导会导致白细胞介素2的转录。现在我们报道，FK506、CsA、雷帕霉素和506BD对IgE受体介导的信号转导具有相同的活性谱，该信号转导会导致大鼠嗜碱性白血病细胞系RBL - 2H3（一种肥大细胞模型）分泌颗粒的胞吐作用。FK506和CsA均抑制受体介导的胞吐作用（CsA的IC50 = 200 nM；FK506的IC50 = 2 nM），而不影响早期受体相关事件（磷脂酰肌醇的水解、类花生酸的合成与释放、Ca2+的摄取）。相比之下，与FK506具有共同结构元件的雷帕霉素和506BD本身对IgE受体介导的胞吐作用没有影响。然而，这两种化合物均可阻止FK506而非CsA的抑制作用。用FK506、CsA和雷帕霉素基质进行亲和层析表明，在RBL - 2H3细胞中发现的同一组免疫亲和素也存在于Jurkat T细胞和小牛胸腺中；然而，这两种细胞类型中这些蛋白质的相对含量有所不同。这些结果表明，T细胞和肥大细胞的细胞质信号传导中存在一个共同步骤，这可能是一般信号传导机制的一部分。
