Bang H, Müller W, Hans M, Brune K, Swandulla D
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Germany.
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3435-8. doi: 10.1073/pnas.92.8.3435.
The immunophilins of the FK506-binding protein (FKBP) family are intracellular proteins that bind the immunosuppresants FK506 and rapamycin. In this study we show that HMC-1 mast cells sensitized with IgE release FKBP12 upon stimulation with anti-IgE. The release is rapid and not affected by actinomycin D or cycloheximide, suggesting that it is due to exocytosis from a storage compartment. FKBP12 from HMC-1 mast cells exhibits biological activity. When applied extracellularly to human neutrophils, it induces transient changes in the intracellular Ca2+ concentration ([Ca2+]i) due to Ca2+ release from intracellular stores. Inhibition of [Ca2+]i changes by ruthenium red and ryanodine indicates that ryanodine receptor/Ca2+ release channels are involved in FKBP12-induced Ca2+ signaling. Neutrophil activation by mast cell-derived FKBP12 is prevented by complexing FKBP12 with FK506 or rapamycin. These results demonstrate that extracellular FKBP12 functions as a cytokine in cell-to-cell communication. They further suggest a pathophysiological role for FKBP12 as a mediator in immediate or type I hypersensitivity and may have implications for novel therapeutic strategies in the treatment of allergic disorders with FK506 and rapamycin.
FK506结合蛋白（FKBP）家族的亲免蛋白是一类细胞内蛋白，可结合免疫抑制剂FK506和雷帕霉素。在本研究中，我们发现用IgE致敏的HMC-1肥大细胞在抗IgE刺激下会释放FKBP12。这种释放迅速，且不受放线菌素D或放线菌酮的影响，表明它是由于从储存隔室中胞吐所致。HMC-1肥大细胞来源的FKBP12具有生物学活性。当将其细胞外应用于人类中性粒细胞时，由于细胞内钙库释放Ca2+，它会诱导细胞内Ca2+浓度（[Ca2+]i）的短暂变化。钌红和ryanodine对[Ca2+]i变化的抑制表明，ryanodine受体/Ca2+释放通道参与了FKBP12诱导的Ca2+信号传导。通过将FKBP12与FK506或雷帕霉素复合，可防止肥大细胞来源的FKBP12对中性粒细胞的激活。这些结果表明，细胞外的FKBP12在细胞间通讯中起细胞因子的作用。它们进一步提示FKBP12作为速发型或I型超敏反应的介质具有病理生理作用，并且可能对用FK506和雷帕霉素治疗过敏性疾病的新治疗策略具有启示意义。
