Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo
Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo
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DOI：
10.1182/blood-2002-11-3370
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发表时间：
2003-06-01
期刊：
影响因子：
20.3
通讯作者：
Thomson, AW
中科院分区：
文献类型：
--
作者：
Hackstein, H;Taner, T;Thomson, AW
雷帕霉素是一种有效的免疫抑制大环内酯类药物，迄今认为其主要通过抑制淋巴细胞对白介素2(IL-2)和其他生长因子的反应而发挥作用。我们在这里指出，这一观点是不完整的，并提供了RAPA在体外和体内抑制树突状细胞(DC)功能激活的证据。在体外，RAPA抑制小鼠骨髓来源的DC的IL-4依赖的成熟和T细胞刺激活性。这些作用与IL-4受体复合体(CD124，CD132)的两个亚基转录后下调有关，并通过RAPA与其细胞内受体FK506结合蛋白12(FKBP12)的结合而介导。在体内，RAPA影响稳态DC的产生和FMS样酪氨酸3激酶配体(Flt3L)诱导的DC动员。此外，体内注射RAPA会损害DC共刺激分子的上调、促炎细胞因子的产生和T细胞的同种刺激能力。这些新的发现对基于RAPA的慢性DC触发的自身免疫性疾病、移植排斥反应和具有激活的Flt3突变的血液系统恶性肿瘤的治疗具有指导意义。(C)2003年，由美国血液病学会提供。
Rapamycin (RAPA) is a potent immunosuppressive macrolide hitherto believed to mediate its action primarily via suppression of lymphocyte responses to interleukin 2 (IL-2) and other growth factors. We show here that this view is incomplete and provide evidence that RAPA suppresses the functional activation of dendritic cells (DCs) both in vitro and in vivo. In vitro, RAPA inhibits IL-4-dependent maturation and T-cell stimulatory activity of murine bone marrow-derived DCs. These effects are associated with post-transcriptional down-regulation of both subunits of the IL-4 receptor complex (CD124, CD132) and are mediated via binding of RAPA to its intracellular receptor FK506-binding protein 12 (FKBP12). In vivo, RAPA impairs steady-state DC generation and fms-like tyrosine 3 kinase ligand (Flt3L)-induced DC mobilization. In addition, in vivo administration of RAPA impairs DC costimulatory molecule up-regulation, production of proinflammatory cytokines, and T-cell allostimulatory capacity. These novel findings have implications for RAPA-based therapy of chronic DC-triggered autoimmune diseases, transplant rejection, and hematologic malignancies with activating Flt3 mutations. (C) 2003 by The American Society of Hematology.