p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines
p53 Regulates Toll-Like Receptor 3 Expression and Function in Human Epithelial Cell Lines
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DOI：
10.1128/mcb.01202-08
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发表时间：
2008-11-01
影响因子：
5.3
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
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作者：
Taura, Manabu;Eguma, Ayaka;Kai, Hirofumi
toll样受体（TLRs）是微生物病原体的重要传感器和先天免疫反应的介质。虽然tlr的信号转导已被很好地阐明，但其基础调控在很大程度上尚未被探索。本研究表明，肿瘤抑制因子p53通过与TLR3启动子中的p53位点结合，积极调节TLR3的转录，TLR3是病毒双链RNA和poly（I-C）的受体。TLR3在HCT116 p53（-/-）细胞中的表达低于HCT116 p53（-/-）细胞。5-氟尿嘧啶激活p53可增加野生型p53上皮细胞系的TLR3 mRNA，而突变型p53细胞系则无此作用。小干扰RNA敲低p53可降低TLR3的表达。TLR3 mRNA在p53（-/-）小鼠的肝脏和肠道中也低于p53（-/-）小鼠。此外，在HCT116 p53（-/-）细胞中，poly（I- c）诱导的I κ B- α磷酸化、nf - κ B核易位和干扰素调节转录因子3磷酸化急剧减少，表明TLR3调控的两种信号通路失调。因此，在HCT116 p53（-/-）细胞中，poly（I-C）刺激后的白细胞介素-8和β干扰素的诱导受损。这些结果表明p53影响TLR3的表达和功能，并突出了p53在上皮细胞先天免疫应答中的作用。
Toll-like receptors (TLRs) are important sensors of microbial pathogens and mediators of innate immune responses. Although the signal transduction of TLRs is well elucidated, their basal regulation is largely unexplored. Here we show that the tumor suppressor p53 positively regulates the transcription of TLR3, a receptor for viral double-stranded RNA and poly(I-C), by binding to the p53 site in the TLR3 promoter. TLR3 expression was lower in HCT116 p53(-/-) cells than in HCT116 p53(-/-) cells. Activation of p53 by 5-fluorouracil increased the TLR3 mRNA in epithelial cell lines with wild-type p53 but not in cell lines harboring mutant p53. Knockdown of p53 by small interfering RNA decreased the TLR3 expression. TLR3 mRNA was also lower in liver and intestine of p53(-/-) mice than in p53(-/-) mice. Furthermore, the poly(I-C)-induced phosphorylation of I kappa B-alpha, nuclear translocation of NF-kappa B, and phosphorylation of interferon regulatory transcription factor 3, were drastically reduced in HCT116 p53(-/-) cells, indicating a dysregulation of the two signaling pathways governed by TLR3. Consequently, induction of interleukin-8 and beta interferon after poly(I-C) stimulation was impaired in HCT116 p53(-/-) cells. These results suggest that p53 influences TLR3 expression and function and highlight a role of p53 in innate immune response in epithelial cells.