The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells.
The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells.
复制标题
DOI：
10.1158/0008-5472.can-11-4134
复制
发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Resnick MA
中科院分区：
文献类型：
--
作者：
Shatz M;Menendez D;Resnick MA
转录因子p53调节与广泛功能相关的基因，包括先天免疫基因的Toll样受体（TLR）集，表明p53也调节人类免疫应答。TLR家族包括识别病原体相关分子模式（PAMP）并介导先天免疫应答的膜糖蛋白，TLR激动剂被用作癌症治疗中的佐剂。在这里，我们表明，阿霉素，5-氟尿嘧啶，紫外线和电离辐射引起TLR表达的变化，是细胞系和损伤特异性。具体而言，处理诱导的表达变化导致响应于配体刺激的下游细胞因子表达增加。DNA应激物对TLR表达的影响主要由p53介导，并且一些p53癌症相关突变体显著改变TLR基因表达的模式。在测试的所有细胞系中，TLR 3诱导是p53依赖性的，而TLR 9（最应激反应的家族成员）的诱导较少依赖于p53的状态。此外，测试的先天免疫TLR基因家族的10个成员中的每一个都是差异诱导的。因此，我们的研究结果表明，在基于TLR的癌症治疗中，应考虑p53状态、染色体应激和单个TLR的反应性矩阵。
The transcription factor p53 regulates genes associated with a wide range of functions, including the Toll-like receptor (TLR) set of innate immunity genes, suggesting that p53 also modulates the human immune response. The TLR family comprises membrane glycoproteins that recognize pathogen-associated molecular patterns (PAMPs) and mediate innate immune responses, and TLR agonists are being used as adjuvants in cancer treatments. Here, we demonstrate that doxorubicin, 5-fluorouracil, and UV and ionizing radiation elicit changes in TLR expression that are cell line- and damage-specific. Specifically, treatment-induced expression changes led to increased downstream cytokine expression in response to ligand stimulation. The effect of DNA stressors on TLR expression was mainly mediated by p53, and several p53 cancer-associated mutants dramatically altered the pattern of TLR gene expression. In all cell lines tested, TLR3 induction was p53-dependent, while induction of TLR9, the most stress-responsive family member, was less dependent on status of p53. In addition, each of the 10 members of the innate immune TLR gene family tested was differentially inducible. Our findings therefore demonstrate that the matrix of p53 status, chromosome stress, and responsiveness of individual TLRs should be considered in TLR-based cancer therapies.