Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking
Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking
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DOI：
10.1182/blood-2005-03-0854
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发表时间：
2005-10-01
期刊：
影响因子：
20.3
通讯作者：
Howard, OMZ
中科院分区：
文献类型：
--
作者：
Chen, X;Murakami, T;Howard, OMZ
雷公藤内酯醇（TPT）是从一种抗炎中药中提取的一种有效的免疫抑制化合物。药据报道，TPT可抑制自身免疫、同种异体移植物排斥和移植物抗宿主病（GVHD），其疗效先前归因于T细胞的抑制。由于树突状细胞（DC）在T细胞介导的免疫启动中起着重要作用，我们研究了TPT对人单核细胞来源的DC的表型、功能和迁移的影响。在药理学浓度范围内，TPT处理抑制了脂多糖（LPS）诱导的表型变化、成熟DC的特征和白细胞介素-12 β（70）（IL-12 β（70））的产生。因此，TPT处理损害了DC的同种异体刺激功能。此外，LPS刺激的DC对次级淋巴组织趋化因子（SLC）/CC趋化因子配体21（CCL 21）的钙动员和趋化反应在TPT处理的DC中显著低于未处理的DC，与较低的趋化因子受体7（CCR 7）和较高的CCR 5表达相关。TPT可抑制巨噬细胞炎性蛋白-3 β（MIP-3 β）/CCL 19诱导的小鼠皮肤朗格汉斯细胞（LC）的逃逸。TPT的体内给药显著抑制半抗原（异硫氰酸荧光素[FITC]）刺激的小鼠皮肤LC向引流淋巴结的迁移。这些数据为TPT的作用机制提供了新的见解，并表明TPT对DC成熟和运输的抑制有助于其免疫抑制作用。
Triptolide (TPT) is a chemically defined, potent immunosuppressive compound isolated from an anti-inflammatory Chinese herbal. medicine. TPT has been reported to inhibit autoimmunity, allograft rejection, and graft-versus-host disease (GVHD), and its efficacy was previously attributed to the suppression of T cells. Since dendritic cells (DCs) play a major role in the initiation of T-cell-mediated immunity, we studied the effects of TPT on the phenotype, function, and migration of human monocyte-derived DCs. TPT treatment, over a pharmacologic concentration range, inhibited the lipopolysaccharide (LPS)-induced phenotypic changes, characteristic of mature DCs and the production of interieukin-12p(70) (IL-12p(70)). Consequently, the allostimulatory functions of DCs were impaired by TPT treatment. Furthermore, the calcium mobilization and chemotactic responses of LPS-stimulated DCs to secondary lymphoid tissue chemokine (SLC)/CC chemokine ligand 21 (CCL21) were significantly lower in TPT-treated than untreated DCs, in association with lower chemokine receptor 7 (CCR7) and higher CCR5 expression. Egress of Langerhans cells (LCs) from explanted mouse skin in response to macrophage inflammatory protein-3 beta (MIP-3 beta)/CCL19 was arrested by TPT. In vivo administration of TPT markedly inhibited hapten (fluorescein isothiocyanate [FITC])-stimulated migration of mouse skin LCs to the draining lymph nodes. These data provide new insight into the mechanism of action of TPT and indicate that the inhibition of maturation and trafficking of DCs by TPT contributes to its immunosuppressive effects.