Mechanistic insights into impaired dendritic cell function by rapamycin: Inhibition of Jak2/Stat4 signaling pathway
Mechanistic insights into impaired dendritic cell function by rapamycin: Inhibition of Jak2/Stat4 signaling pathway
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DOI：
10.4049/jimmunol.172.3.1355
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发表时间：
2004-02-01
影响因子：
4.4
通讯作者：
Qian, SG
中科院分区：
文献类型：
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作者：
Chiang, PH;Wang, LF;Qian, SG
雷帕霉素对T细胞的抑制作用已被广泛研究，但其对APC功能的影响尚不清楚。本研究中的数据表明，暴露于雷帕霉素 (rapa-DC) 的 B10 (H2(b)) 树突状细胞 (DC) 的免疫刺激活性明显受到抑制，同种异体 (C3H, H2(k)) T 细胞中诱导低增殖反应和特异性 CTL 活性证明了这一点。给予 rapa-DC 显着延长了 C3H 受体中 B10 同种异体心脏移植物的存活率。雷帕霉素处理不影响 DC II 类 MHC 和共刺激分子的表达或 IL-12 的产生。雷帕霉素不抑制 DC NF-kappaB 通路，但通过 Janus 激酶 2/Stat4 激活的 IL-12 信号传导被显着抑制。事实上，Stat4(-/-) DC 同样表现出较差的同种刺激活性。 Stat4下游产物IFN-γ也被雷帕霉素抑制，但DC功能障碍不能仅仅归因于IFN-γ产量低，因为IFN-γ缺陷的DC仍然表现出旺盛的同种刺激活性。雷帕霉素不影响 DC IL-12R 表达，但显着抑制 IL-18Rα 和 β 表达，这可能反过来下调 DC IL-12 自分泌激活。
The suppressive effect of rapamycin on T cells has been extensively studied, but its influence on the function of APC is less clear. The data in this study demonstrated that immunostimulatory activity of B10 (H2(b)) dendritic cells (DC) exposed to rapamycin (rapa-DC) was markedly suppressed as evidenced by the induction of low proliferative responses and specific CTL activity in allogeneic (C3H, H2(k)) T cells. Administration of rapa-DC significantly prolonged survival of B10 cardiac allografts in C3H recipients. Treatment with rapamycin did not affect DC expression of MHC class II and costimulatory molecules or IL-12 production. Rapamycin did not inhibit DC NF-kappaB pathway, however, IL-12 signaling through Janus kinase 2/Stat4 activation was markedly suppressed. Indeed, Stat4(-/-) DC similarly displayed poor allostimulatory activity. The Stat4 downstream product, IFN-gamma, was also inhibited by rapamycin, but DC dysfunction could not solely be attributed to low IFN-gamma production as DC deficient in IFN-gamma still exhibited vigorous allostimulatory activity. Rapamycin did not affect DC IL-12R expression, but markedly suppressed IL-18Ralpha and beta expression, which may in turn down-regulate DC IL-12 autocrine activation.