Dumont F J, Melino M R, Staruch M J, Koprak S L, Fischer P A, Sigal N H
Department of Immunology Research, Merck, Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
J Immunol. 1990 Feb 15;144(4):1418-24.
The structurally related immunosuppressive macrolides FK-506 and rapamycin (RAP) were previously shown to inhibit T cell stimulation through different mechanisms. FK-506 acts similarly to cyclosporin A (CsA) and prevents IL-2 production and IL-2R expression. RAP has little or no effect on these events but markedly impedes the response to IL-2. The present study was initiated to examine the possibility of a complementation between the immunosuppressive actions of RAP and FK-506 or CsA on various murine T cell responses. RAP potentiated the effect of CsA on proliferation and IL-2R expression in T cells stimulated with ionomycin + PMA. However, in the same system, RAP acted as a potent antagonist of FK-506 suppression. RAP also blocked FK-506- but not CsA-mediated inhibition of IL-2 mRNA induction. By using model systems sensitive to inhibition by RAP but not FK-506 we further demonstrated that FK-506 reciprocally behaves as an antagonist of RAP. In one such model, the stimulation of splenic T cells with IL-2 + PMA, FK-506, but not CsA, reversed the suppressive effect of RAP on proliferation. FK-506 also antagonized RAP-mediated inhibition with respect to the induction of Ly-6E Ag expression by IFN in YAC cells. To explore further the competition between the two macrolides at the cellular level, we performed binding experiments with a radiolabeled derivative of FK-506. Both FK-506 and RAP, but not CsA, inhibited the binding of this probe in YAC cells. Taken together, these data demonstrate that FK-506 and RAP antagonize each other's biologic activity and physically interact with a common receptor site(s) in T cells. Moreover, CsA acts at a site distinct from the cellular target(s) of FK-506 or RAP.
结构相关的免疫抑制大环内酯类药物FK-506和雷帕霉素（RAP）先前已被证明通过不同机制抑制T细胞刺激。FK-506的作用类似于环孢素A（CsA），可阻止IL-2的产生和IL-2R的表达。RAP对这些事件几乎没有影响，但会显著阻碍对IL-2的反应。本研究旨在探讨RAP与FK-506或CsA的免疫抑制作用在各种小鼠T细胞反应中互补的可能性。RAP增强了CsA对离子霉素+佛波酯刺激的T细胞增殖和IL-2R表达的作用。然而，在同一系统中，RAP作为FK-506抑制作用的有效拮抗剂。RAP还阻断了FK-506介导的IL-2 mRNA诱导抑制作用，但未阻断CsA介导的抑制作用。通过使用对RAP抑制敏感但对FK-506不敏感的模型系统，我们进一步证明FK-506反过来也表现为RAP的拮抗剂。在一个这样的模型中，用IL-2 +佛波酯刺激脾T细胞，FK-506而非CsA可逆转RAP对增殖的抑制作用。FK-506还拮抗了RAP介导的关于IFN诱导YAC细胞中Ly-6E Ag表达的抑制作用。为了在细胞水平上进一步探索这两种大环内酯类药物之间的竞争，我们用FK-506的放射性标记衍生物进行了结合实验。FK-506和RAP均可抑制该探针在YAC细胞中的结合，但CsA无此作用。综上所述，这些数据表明FK-506和RAP相互拮抗彼此的生物学活性，并在T细胞中与共同的受体位点发生物理相互作用。此外，CsA作用于与FK-506或RAP的细胞靶点不同的位点。
