Rb/E2F1 regulates the innate immune receptor Toll-like receptor 3 in epithelial cells
Rb/E2F1 regulates the innate immune receptor Toll-like receptor 3 in epithelial cells
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Rb/E2F1 调节上皮细胞中的先天免疫受体 Toll 样受体 3
DOI：
10.1128/mcb.06454-11
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发表时间：
2012
影响因子：
5.3
通讯作者：
et.al.
中科院分区：
文献类型：
--
作者：
Taura M.;et.al.
肿瘤抑制基因通过尚未充分探索的分子机制调节抗病毒宿主防御。在这里，我们发现肿瘤抑制视网膜母细胞瘤 (Rb) 蛋白正向调节 Toll 样受体 3 (TLR3) 的表达，Toll 样受体 3 (TLR3) 是病毒双链 RNA 和聚 (I·C) 的传感受体。 Rb 敲除 (Rb−/−) 小鼠胚胎成纤维细胞 (MEF) 和转染 Rb 小干扰 RNA (siRNA) 的哺乳动物上皮细胞中的 TLR3 表达低于对照细胞。因此，与对照组相比，在 Rb−/−MEF 和 Rb siRNA 转染细胞中，聚 (I·C) 刺激后细胞因子白细胞介素 8 和 β 干扰素的诱导受到损害。 TLR3 启动子分析表明，Rb 调节转录因子 E2F1，该因子直接与 TLR3 的近端启动子结合。外源添加 E2F1 会降低 TLR3 启动子活性，而 Rb 剂量依赖性地抑制 E2F1 的作用。有趣的是，poly(I·C) 增加了 Rb 表达，而在 Rb 耗尽的细胞中，poly(I·C) 诱导的 TLR3 表达受损，这表明 Rb 在 poly(I·C) 诱导 TLR3 中的重要性。总之，这些数据表明 E2F1 抑制 TLR3 转录，但在免疫刺激过程中，Rb 上调以阻断 E2F1 对 TLR3 的抑制作用，突出了 Rb-E2F1 轴在上皮细胞先天免疫反应中的作用。
Tumor suppressor genes regulate the antiviral host defense through molecular mechanisms that are not yet well explored. Here, we show that the tumor suppressor retinoblastoma (Rb) protein positively regulates Toll-like receptor 3 (TLR3) expression, the sensing receptor for viral double-stranded RNA and poly(I·C). TLR3 expression was lower in Rb knockout (Rb−/−) mouse embryonic fibroblasts (MEF) and in mammalian epithelial cells transfected with Rb small-interfering RNA (siRNA) than in control cells. Consequently, induction of cytokines interleukin-8 and beta interferon after poly(I·C) stimulation was impaired in Rb−/−MEF and Rb siRNA-transfected cells compared to controls. TLR3 promoter analysis showed that Rb modulates the transcription factor E2F1, which directly binds to the proximal promoter of TLR3. Exogenous addition of E2F1 decreased TLR3 promoter activity, while Rb dose dependently curbed the effect of E2F1. Interestingly, poly(I·C) increased the Rb expression, and the poly(I·C)-induced TLR3 expression was impaired in Rb-depleted cells, suggesting the importance of Rb in TLR3 induction by poly(I·C). Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells.