2 DISTINCT SIGNAL TRANSMISSION PATHWAYS IN LYMPHOCYTES-T ARE INHIBITED BY COMPLEXES FORMED BETWEEN AN IMMUNOPHILIN AND EITHER FK506 OR RAPAMYCIN
2 DISTINCT SIGNAL TRANSMISSION PATHWAYS IN LYMPHOCYTES-T ARE INHIBITED BY COMPLEXES FORMED BETWEEN AN IMMUNOPHILIN AND EITHER FK506 OR RAPAMYCIN
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DOI：
10.1073/pnas.87.23.9231
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发表时间：
1990-12-01
影响因子：
11.1
通讯作者：
SCHREIBER, SL
中科院分区：
文献类型：
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作者：
BIERER, BE;MATTILA, PS;SCHREIBER, SL
T淋巴细胞的增殖和免疫功能是由抗原受体发出的信号启动的，抗原受体被免疫抑制剂FK506抑制，但不被其结构类似物雷帕霉素抑制。另一方面，白细胞介素2 （IL-2）诱导的信号被雷帕霉素阻断，而不被FK506阻断。值得注意的是，这两种药物相互抑制作用，提高了两者通过共同的亲免疫蛋白（免疫抑制结合蛋白）起作用的可能性。我们发现，雷帕霉素对FK506结合蛋白FKBP的解离常数（Kd = 0.2 nM）与FK506对FKBP的解离常数（Kd = 0.4 nM）及其有效生物抑制浓度接近。然而，过量的雷帕霉素需要恢复fk506介导的对IL-2产生、凋亡和NF-AT （IL-2基因激活所必需的t细胞特异性转录因子）转录激活的抑制。同样，需要过量的FK506来恢复雷帕霉素介导的il -2诱导的增殖抑制。拮抗所需的药物浓度可以用药物与亲免疫蛋白FKBP的相对亲和力和丰度来解释。FKBP已被证明可以催化肽底物的肽基-丙烯酰胺键的顺式和反式旋转体的相互转化；我们发现雷帕霉素和FK506一样，是FKBP轮状酶活性的有效抑制剂（Ki = 0.2 nM）。无论是FKBP结合还是单独抑制FKBP的轮状酶活性都不足以解释这些药物的生物学作用。相反，这些发现表明，与FK506结合的亲免疫蛋白会干扰抗原受体诱导的信号，而与亲免疫蛋白结合的雷帕霉素会干扰il -2诱导的信号。
Proliferation and immunologic function of T lymphocytes are initiated by signals from the antigen receptor that are inhibited by the immunosuppressant FK506 but not by its structural analog, rapamycin. On the other hand, interleukin 2 (IL-2)-induced signals are blocked by rapamycin but not by FK506. Remarkably, these two drugs inhibit each other''s actions, raising the possibility that both act by means of a common immunophilin (immunosuppressant binding protein). We find that the dissociation constant of rapamycin to the FK506 binding protein FKBP (Kd = 0.2 nM) is close to the dissociation constant of FK506 to FKBP (Kd = 0.4 nM) and to their effective biologic inhibitory concentrations. However, an excess of rapamycin is needed to revert FK506-mediated inhibition of IL-2 production, apoptosis, and transcriptional activation of NF-AT, a T-cell-specific transcription factor necessary for IL-2 gene activation. Similarly, an excess of FK506 is needed to revert rapamycin-mediated inhibition of IL-2-induced proliferation. The drug concentrations required for antagonism may be explained by the relative affinity of the drugs to, and by the abundance of, the immunophilin FKBP. FKBP has been shown to catalyze the interconversion of the cis- and trans-rotamers of the peptidyl-prolyl amide bond of peptide substrates; where we show that rapamycin, like FK506, is a potent inhibitor of the rotamase activity of FKBP (Ki = 0.2 nM). Neither FKBP binding nor inhibition of rotamase activity of FKBP alone is sufficient to explain the biologic actions of these drugs. Rather, these findings suggest that immunophilin bound to FK506 interferes with antigen receptor-induced signals, while rapamycin bound to the immunophilin interferes with IL-2-induced signals.