Toll-like receptor priming sensitizes macrophages to proinflammatory cytokine gene induction by deoxynivalenol and other toxicants
Toll-like receptor priming sensitizes macrophages to proinflammatory cytokine gene induction by deoxynivalenol and other toxicants
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DOI：
10.1093/toxsci/kfl012
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发表时间：
2006-08-01
影响因子：
3.8
通讯作者：
Zhou, Hui-Ren
中科院分区：
文献类型：
--
作者：
Pestka, James;Zhou, Hui-Ren
先天免疫系统的激活可能使宿主易于发生毒物诱导的炎症。采用体外巨噬细胞模型研究Toll样受体（TLR）激动剂预暴露对由槲皮素真菌毒素脱氧雪腐镰刀菌烯醇（DON）和其他毒物诱导的促炎细胞因子基因表达的影响。与单独的LPS或DON相比，用100 ng/ml的TLR 4激动剂脂多糖（LPS）引发鼠RAW 264.7巨噬细胞系或腹膜鼠巨噬细胞4、8和16 h显著增加了DON诱导的IL-1 β、IL-6和TNF-α mRNA表达。致敏两种细胞类型的最小LPS浓度为1 ng/ml。在人全血培养物中，LPS引发也增强了DON对IL-1 β mRNA的诱导，这表明了小鼠研究结果的相关性。如对于LPS所观察到的，预暴露于TLR激动剂，包括酵母聚糖（TLR 2）、poly（I：C）（TLR 3）、鞭毛蛋白（TLR 5）、R848（TLR 7/8）和ODN 1826（TLR 9），使RAW 267.4细胞对DON诱导的促炎基因表达敏感。在暴露于微生物毒素satratoxin G、滋贺毒素和玉米赤霉烯酮以及人为毒物氯化镍、三苯基锡、2，4-二硝基氯苯和2，3，7，8-四氯二苯并二恶英的LPS致敏RAW 264.7细胞中，也同样证明了促炎性mRNA表达的扩增。结果表明，先前TLR激活可能使巨噬细胞对具有不同作用机制的外源性物质随后诱导促炎基因表达高度敏感。
Activation of the innate immune system might predispose a host to toxicant-induced inflammation. In vitro macrophage models were employed to investigate the effects of preexposure to Toll-like receptor (TLR) agonists on induction of proinflammatory cytokine gene expression by the trichothecene mycotoxin deoxynivalenol (DON) and other toxicants. Priming of the murine RAW 264.7 macrophage line or peritoneal murine macrophages with the TLR4 agonist lipopolysaccharide (LPS) at 100 ng/ml for 4, 8, and 16 h significantly increased DON-induced IL-1 beta, IL-6, and TNF-alpha mRNA expression as compared to LPS or DON alone. The minimum LPS concentration for sensitization of both cell types was 1 ng/ml. LPS priming also potentiated IL-1 beta mRNA induction by DON in human whole-blood cultures, suggesting the relevance of the murine findings. As observed for LPS, preexposure to TLR agonists including zymosan (TLR2), poly (I:C) (TLR3), flagellin (TLR5), R848 (TLR7/8), and ODN1826 (TLR9) sensitized RAW 267.4 cells to DON-induced proinflammatory gene expression. Amplified proinflammatory mRNA expression was similarly demonstrated in LPS-sensitized RAW 264.7 cells exposed to the microbial toxins satratoxin G, Shiga toxin, and zearalenone as well as the anthropogenic toxicants nickel chloride, triphenyltin, 2,4-dinitrochlorobenzene, and 2,3,7,8-tetrachlorodibenzodioxin. The results suggest that prior TLR activation might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action.