Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells.
Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells.
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DOI：
10.2147/jir.s61365
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发表时间：
2014
影响因子：
4.5
通讯作者：
Malathi K
中科院分区：
文献类型：
--
作者：
Mukherjee S;Siddiqui MA;Dayal S;Ayoub YZ;Malathi K
前列腺的慢性炎症会增加患前列腺癌的风险。前列腺中的微生物病原体引起炎症，导致前列腺炎和增殖性炎症萎缩，通常与前列腺癌的发展相关。细菌脂多糖和 DNA 分别通过结合 Toll 样受体 (TLR) 4 和 9 介导免疫反应。含有 CpG 基序 (CpG-ODN) 的合成寡脱氧核苷酸模仿细菌 DNA 并通过 TLR9 发出信号以启动先天免疫反应。在这里，我们发现 TLR9 激动剂 CpG-ODN 刺激 DU145、PC3 或 LnCap 前列腺癌细胞可诱导 IL-6、IL-8、CXCL1、IP-10、CCL5 和 TGFβ 的 mRNA 表达。此外，CpG-ODN 处理后基质金属蛋白酶 (MMP)-9 和 -2 的活性以及细胞迁移增加。细胞因子和趋化因子的诱导是由 NF-κB 激活和易位至细胞核介导的。在 CpG-ODN 刺激之前，用绿茶的主要成分表没食子儿茶素-3-没食子酸酯 (EGCG) 进行处理，可抑制细胞因子和趋化因子基因诱导、MMP-9 和 -2 的活性以及细胞迁移。 EGCG 处理将转录因子 NF-κB 的 p65 亚基隔离在细胞质中，并抑制 NF-κB 驱动的启动子响应 CpG-ODN 的转录活性。我们的结果表明，TLR9 激动剂 CpG-ODN 诱导细胞因子、趋化因子和 MMP 活性以及 EGCG 抑制的能力与细胞的雄激素受体和 p53 状态无关。 EGCG 可以提供针对前列腺炎症的保护作用，并有利于前列腺癌的治疗。
Chronic inflammation of the prostate contributes to the increased risk of prostate cancer. Microbial pathogens in the prostate cause inflammation that leads to prostatitis and proliferative inflammatory atrophy frequently associated with the development of prostate cancer. Bacterial lipopolysaccharides and DNA mediate immune responses by engaging Toll-like receptor (TLR) 4 and 9, respectively. Synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) mimic bacterial DNA and signal through TLR9 to initiate innate immune responses. Here, we show that stimulation of DU145, PC3, or LnCap prostate cancer cells by the TLR9 agonists, CpG-ODN, induces mRNA expression of IL-6, IL-8, CXCL1, IP-10, CCL5, and TGFβ. In addition, activity of matrix metalloproteinase (MMP)-9 and -2 and cell migration increased on CpG-ODN treatment. Induction of cytokines and chemokines was mediated by NF-κB activation and translocation to the nucleus. Treatment with epigallocatechin-3-gallate (EGCG), the major constituent of green tea, prior to CpG-ODN stimulation, inhibits cytokine and chemokine gene induction, activity of MMP-9 and -2, and cell migration. EGCG treatment sequesters the p65 subunit of transcription factor NF-κB in the cytoplasm and inhibits transcriptional activity of the NF-κB-driven promoter in response to CpG-ODN. Our results suggest that the ability of the TLR9 agonists, CpG-ODN, to induce cytokines, chemokines, and MMP activity, as well as suppression by EGCG are independent of the androgen receptor and p53 status of the cells. EGCG may provide protective effects against inflammation in the prostate and benefit prostate cancer treatment.