Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3
Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3
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DOI：
10.4049/jimmunol.0902579
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发表时间：
2010-01-15
影响因子：
4.4
通讯作者：
Nakai, Akira
中科院分区：
文献类型：
--
作者：
Takii, Ryosuke;Inouye, Sachiye;Nakai, Akira
发热反应是对疾病的一种复杂的生理反应，包括细胞因子介导的体温升高和炎症系统的激活。发烧在疾病预后方面有有益的作用，部分是通过抑制炎性细胞因子的表达。然而，发热介导的抑制炎症基因表达的分子机制尚不清楚。在本研究中，我们发现热休克抑制了内毒素诱导的小鼠胚胎成纤维细胞和巨噬细胞中IL-6的表达，IL-6是一种主要的致热细胞因子。热休克激活的转录因子1(HSF1)诱导IL-6的负调控因子激活转录因子(ATF)3的表达，而ATF3是热介导的IL-6抑制所必需的，表明由HSF1和ATF3组成的发热介导的反馈环。对炎症基因表达的综合分析显示，热预处理可抑制大多数(86%)内毒素诱导的基因表达，部分(67%)是通过ATF3实现的。当HSF1基因缺失和ATF3基因缺失的小鼠注射脂多糖时，它们的IL-6水平比野生型小鼠高得多，导致了夸大的发热反应。这些结果为炎性细胞因子提供了一种新的抑制途径。免疫学杂志，2010,184：1041-1048。
The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines. The Journal of Immunology, 2010, 184: 1041-1048.