Hom J T, Estridge T
Department of Pulmonary and Leukotriene Research, Lilly Research Laboratories, Indianapolis, Indiana 46285.
Clin Immunol Immunopathol. 1993 Sep;68(3):293-300. doi: 10.1006/clin.1993.1130.
Numerous studies suggest that eosinophils may play a role in the inflammatory process of various diseases. Eosinophils are potent effectors of a variety of end-stage inflammatory activities. In addition, eosinophils are highly capable of synthesizing several cytokines which can stimulate the inflammatory responses of other cell types. Eosinophils are also responsive to a number of cytokines in that their in vitro survival as well as their effector functions can be enhanced by various cytokines. Finally, it is well established that the immunosuppressive drugs, FK506 and rapamycin, can inhibit the activation of T cells and mast cells. In the present study, the effects of FK506 and rapamycin on the activities of human peripheral blood eosinophils were investigated. It was first shown that human peripheral blood eosinophils upon stimulation with the calcium ionophore A23187 produced significant amounts of the cytokines, GM-CSF and IL3. FK506 was found to inhibit the synthesis of IL3 and GM-CSF, whereas rapamycin failed to suppress the cytokine production of eosinophils. Since FK506 and rapamycin are structurally related, the ability of rapamycin to reverse the FK506-mediated inhibition on cytokine production of eosinophils was next examined. It was observed that a 250-fold excess of rapamycin was required to antagonize the suppressive effects of FK506 on the cytokine secretion mediated by eosinophils. The capacity of rapamycin to alter the in vitro IL5-mediated survival of eosinophils was also studied. The results of this study demonstrated that rapamycin was effective in reducing the ability of IL5 to maintain the survival of eosinophils in culture; by contrast, FK506 had minimal effects on the IL5-mediated survival of eosinophils. In conclusion, the effects of FK506 and rapamycin on the activities of eosinophils appear to parallel those of mast cells and T cells. Hence, it is possible that FK506 and rapamycin might be acting on signal pathways or molecules that are shared by eosinophils, mast cells as well as T cells. Moreover, these findings suggest that both FK506 and rapamycin can potentially interfere with the capacity of eosinophils to engage in interactive activities that may contribute to the chronicity of inflammatory diseases such as asthma.
大量研究表明，嗜酸性粒细胞可能在多种疾病的炎症过程中发挥作用。嗜酸性粒细胞是多种终末期炎症活动的强效效应细胞。此外，嗜酸性粒细胞能够高效合成多种细胞因子，这些细胞因子可刺激其他细胞类型的炎症反应。嗜酸性粒细胞对多种细胞因子也有反应，因为各种细胞因子可增强其体外存活能力及其效应功能。最后，众所周知，免疫抑制药物FK506和雷帕霉素可抑制T细胞和肥大细胞的活化。在本研究中，研究了FK506和雷帕霉素对人外周血嗜酸性粒细胞活性的影响。首先发现，人外周血嗜酸性粒细胞在用钙离子载体A23187刺激后会产生大量细胞因子GM-CSF和IL3。发现FK506可抑制IL3和GM-CSF的合成，而雷帕霉素未能抑制嗜酸性粒细胞的细胞因子产生。由于FK506和雷帕霉素在结构上相关，接下来研究了雷帕霉素逆转FK506介导的对嗜酸性粒细胞细胞因子产生抑制作用的能力。观察到需要250倍过量的雷帕霉素才能拮抗FK506对嗜酸性粒细胞介导的细胞因子分泌的抑制作用。还研究了雷帕霉素改变体外IL5介导的嗜酸性粒细胞存活的能力。本研究结果表明，雷帕霉素可有效降低IL5维持培养中嗜酸性粒细胞存活的能力；相比之下，FK506对IL5介导的嗜酸性粒细胞存活影响极小。总之，FK506和雷帕霉素对嗜酸性粒细胞活性的影响似乎与肥大细胞和T细胞的影响相似。因此，FK506和雷帕霉素可能作用于嗜酸性粒细胞、肥大细胞以及T细胞共有的信号通路或分子。此外，这些发现表明，FK506和雷帕霉素都可能潜在地干扰嗜酸性粒细胞参与可能导致哮喘等炎症性疾病慢性化的相互作用活动的能力。
