The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA
The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA
复制标题
DOI：
10.1002/eji.201242699
复制
发表时间：
2013-01-01
影响因子：
5.4
通讯作者：
Kadowaki, Norimitsu
中科院分区：
文献类型：
--
作者：
Fujita, Haruyuki;Kitawaki, Toshio;Kadowaki, Norimitsu
浆细胞样树突状细胞（pDC）通过Toll样受体（TLR）7和TLR 9响应来自病毒和受损自身细胞的核酸而产生大量干扰素（IFN）-α。抑制pDC产生IFN-α的药剂有助于阐明IFN-α产生背后的机制，并有助于开发涉及pDC的炎性疾病的新疗法。在这里，我们表明，酪氨酸激酶抑制剂的慢性髓细胞白血病与多个目标，达沙替尼，强烈抑制生产IFN-α和促炎细胞因子的人pDC刺激多聚体CpG寡脱氧核苷酸（CpG-A），而不降低活力。相反，其他酪氨酸激酶抑制剂伊马替尼和尼洛替尼在临床相关浓度下不抑制细胞因子的产生。SRC家族激酶（SFK）抑制剂是达沙替尼的主要靶点，也可抑制细胞因子的产生。然而，值得注意的是，达沙替尼而不是SFK抑制剂消除了CpG-A在早期内体中的长期定位，这是pDC产生大量IFN-α的关键步骤。这项研究表明，达沙替尼通过抑制SFK依赖性途径和CpG DNA的SFK非依赖性内体滞留来抑制pDC产生IFN-α。控制pDC中独特的内体运输的激酶可被用作开发用于pDC相关炎性病症的新疗法的靶标。
Plasmacytoid dendritic cells (pDCs) produce a vast amount of interferon (IFN)-a in response to nucleic acids from viruses and damaged self-cells through Toll-like receptor (TLR)7 and TLR9. Pharmaceutical agents that suppress IFN-a production by pDCs are instrumental in elucidating the mechanisms behind IFN-a production, and in developing novel therapies for inflammatory disorders that involve pDCs. Here, we show that a tyrosine kinase inhibitor for chronic myeloid leukemia with multiple targets, dasatinib, strongly suppresses production of IFN-a and proinflammatory cytokines by human pDCs stimulated with multimeric CpG oligodeoxynucleotides (CpG-A) without reducing viability. In contrast, other tyrosine kinase inhibitors, imatinib, and nilotinib, did not suppress the cytokine production at clinically relevant concentrations. Inhibitors of SRC family kinases (SFKs), which are prominent targets of dasatinib, also suppressed the cytokine production. Notably, however, dasatinib, but not SFK inhibitors, abrogated prolonged localization of CpG-A in early endosomes, which is a critical step for pDCs to produce a large amount of IFN-a. This study suggests that dasatinib suppresses IFN-a production by pDCs by inhibiting SFK-dependent pathways and SFK-independent endosomal retention of CpG DNA. Kinases controlling the distinctive endosomal trafficking in pDCs may be exploited as targets to develop novel therapies for pDC-related inflammatory disorders.