Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-κB pathways
Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-κB pathways
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DOI：
10.1016/j.molimm.2006.12.003
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发表时间：
2007-04-01
影响因子：
3.6
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Qiuyan;Chen, Taoyong;Cao, Xuetao
抑制树突状细胞向组织和次级淋巴器官的迁移是诱导免疫抑制和耐受的有效途径。CCR7和PGE(2)是DC向次级淋巴器官迁移的关键，DC在次级淋巴器官引发免疫应答。雷公藤甲素是一种从药用植物雷公藤中纯化的活性成分，是一种有效的免疫抑制药物，能够通过抑制T细胞的活化和增殖来延长器官移植中同种异体移植物的存活时间。考虑到DC向次级淋巴器官迁移在T细胞耐受中的重要作用，本研究证明雷公藤甲素可以通过抑制DC中环氧合酶-2 （COX-2）的表达，显著抑制lps触发的CCR7表达上调和PGE(2)的产生，从而在体外损害DC向CCR7配体CCL19/M1P-3 β的迁移。此外，雷公藤甲素处理的DC向次级淋巴器官的迁移受到损害，体内给药雷公藤甲素也会抑制DC的迁移。进一步的研究表明，雷公雷甲素介导的脂多糖诱导的磷脂酰肌醇-3激酶(PI3-K)/Akt活化和核NF-kappa B活化的抑制作用参与了下调COX-2和CCR7的表达，导致DC向次级淋巴器官的迁移受损。因此，通过PI3-K/Akt和NF-kappa B信号通路降低COX-2和CCR7的表达来抑制DC迁移，为雷公藤甲素的免疫抑制作用提供了额外的机制解释。(c) 2006 Elsevier Ltd.版权所有。
Inhibition of dendritic cell (DC) migration into tissues and secondary lymphoid organs is an efficient way to induce immunosuppression and tolerance. CCR7 and PGE(2) are critical for DC migration to secondary lymphoid organs where DC initiate immune response. Triptolide, an active component purified from the medicinal plant Tripterygium Wilfordii Hook F., is a potent immunosuppressive drug capable of prolonging allograft survival in organ transplantation by inhibiting T cell activation and proliferation. Considering the essential role in T cell tolerance of DC migration to secondary lymphoid organs, here we demonstrate that triptolide can significantly inhibit LPS-triggered upregulation of CCR7 expression and PGE(2) production by inhibiting cyclooxygenase-2 (COX-2) expression in DC, thus impairing DC migration towards CCR7 ligand CCL19/M1P-3 beta in vitro. Moreover, triptolide-treated DC display impaired migration into secondary lymphoid organs and in vivo administration of triptolide also inhibits DC migration. Further studies show that the triptolide-mediated inhibitory effects of LPS-induced activation of phosphatidylinositol-3 kinase (PI3-K)/Akt and nuclear NF-kappa B activation are involved in down-regulation of COX-2 and CCR7 expression resulting in impaired migration to secondary lymphoid organs of DC. Therefore, inhibition of DC migration through decreasing COX-2 and CCR7 expression via PI3-K/Akt and NF-kappa B signal pathways provides additional mechanistic explanation for triptolide's immunosuppressive effect. (c) 2006 Elsevier Ltd. All rights reserved.