TLR3 can directly trigger apoptosis in human cancer cells
TLR3 can directly trigger apoptosis in human cancer cells
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DOI：
10.4049/jimmunol.176.8.4894
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发表时间：
2006-04-15
影响因子：
4.4
通讯作者：
Renno, Toufic
中科院分区：
文献类型：
--
作者：
Salaun, Bruno;Coste, Isabelle;Renno, Toufic
TLR 充当分子传感器，检测病原体衍生产物并触发保护性反应，包括分泌增加受感染细胞抵抗力的细胞因子和招募免疫细胞的趋化因子，以及限制微生物传播的细胞死亡。病毒dsRNA参与病毒感染的细胞凋亡，但所涉及的信号通路仍不清楚。在这项研究中，我们证明合成的 dsRNA 以 TLR3 依赖性方式诱导人乳腺癌细胞凋亡，该方式涉及分子接头 Toll/IL-1R 结构域的接头诱导 IFN-β 和 I 型 IFN 自分泌信号传导，但发生独立于 dsRNA 激活激酶。此外，对 dsRNA 诱导的细胞死亡的详细分子分析确定了 TLR3 下游的 IL-1R 相关激酶 4 和 NF-κ B 的促凋亡作用以及外源性半胱天冬酶的激活。癌细胞表达的内源性人 TLR3 的直接促凋亡活性揭示了多面 TLR 生物学的一个新方面，这可能为使用 TLR3 激动剂作为选定癌症的细胞毒剂开辟新的临床前景。
TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading. Viral dsRNA participate in virus-infected cell apoptosis, but the signaling pathway involved remains unclear. In this study we show that synthetic dsRNA induces apoptosis of human breast cancer cells in a TLR3-dependent manner, which involves the molecular adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta and type I IFN autocrine signaling, but occurs independently of the dsRNA-activated kinase. Moreover, detailed molecular analysis of dsRNA-induced cell death established the proapoptotic role of IL-1R-associated kinase-4 and NF-kappa B downstream of TLR3 as well as the activation of the extrinsic caspases. The direct proapoptotic activity of endogenous human TLR3 expressed by cancerous cells reveals a novel aspect of the multiple-faced TLR biology, which may open new clinical prospects for using TLR3 agonists as cytotoxic agents in selected cancers.