Evidence for a role of heat shock factor 1 in inhibition of NF-κB pathway during heat shock response-mediated lung protection
Evidence for a role of heat shock factor 1 in inhibition of NF-κB pathway during heat shock response-mediated lung protection
复制标题
DOI：
10.1152/ajplung.00184.2003
复制
发表时间：
2004-11-01
影响因子：
4.9
通讯作者：
Gustin, P
中科院分区：
文献类型：
--
作者：
Wirth, D;Bureau, F;Gustin, P
热休克转录因子 (HSF)-1 被认为是热休克反应的核心成分，可防止各种有害状况。然而，HSF-1 的保护机制以及 HSF-1 在这些机制中的作用尚未明确阐明。使用 HSF-1 敲除小鼠 (Hsf1(-/-))，我们检查了热休克反应介导的肺保护是否涉及通过 HSF-1 和 NF-kappaB 之间的相互作用抑制促炎途径，以应对镉损伤。 HSF-1 依赖性的针对镉鼻内滴注（10 和 100 杯/小鼠）的保护作用通过支气管肺泡液中较高的蛋白质含量（1.2 倍和 1.4 倍）、巨噬细胞（1.6 倍和 1.9 倍）和中性粒细胞（2.6 倍和 1.8 倍）数量、更高的肺湿干重比和更严重的肺部表现来证明。损害评估由 Hsf1(-/-) 与野生型动物的组织病理学比较。与野生型动物相比，这些反应与 Hsf1(-/-) 小鼠支气管肺泡液中较高的粒细胞/巨噬细胞集落刺激因子 (GM-CSF；1.7 倍) 浓度相关，但与 TNF-α 浓度无关，表明 HSF-1 在我们的模型中充当特定细胞因子产生的抑制因子。为了进一步研究 GM-CSF 抑制机制，我们分析了 NF-kappaB 活性和 IkappaB 稳定性。镉暴露后，Hsf1(-/-) 小鼠的 DNA 结合 NF-κB 活性，特别是 p50 同二聚体活性高于野生型小鼠。这些结果提供了第一线证据，表明依赖于 HSF-1 的肺保护机制涉及通过抑制体内 NF-κB 激活来抑制特定的细胞因子。
Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the protection and the role of HSF-1 in these mechanisms have not yet been clearly elucidated. Using HSF-1 knockout mice (Hsf1(-/-)), we examined whether heat shock response-mediated lung protection involved an inhibition of the proinflammatory pathway via an interaction between HSF-1 and NF-kappaB, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 mug/mouse) was demonstrated by the higher protein content (1.2- and 1.4-fold), macrophage (1.6- and 1.9-fold), and neutrophil (2.6- and 1.8-fold) number in bronchoalveolar fluids, higher lung wet-to-dry weight ratio, and more severe lung damage evaluated by histopathology in Hsf1(-/-) compared with wild-type animals. These responses were associated with higher granulocyte/macrophage colony-stimulating factor (GM-CSF; 1.7-fold) but not TNF-alpha concentrations in bronchoalveolar fluids of Hsf1(-/-) mice compared with those of wild-type animals, indicating that HSF-1 behaved as a repressor of specific cytokine production in our model. To further investigate the mechanism of GM-CSF repression, we analyzed the NF-kappaB activity and IkappaB stability. The DNA binding NF-kappaB activity, in particular p50 homodimer activity, was higher in Hsf1(-/-) mice than in wild-type mice after cadmium exposure. These results provide a first line of evidence that mechanisms of lung protection depending on HSF-1 involve specific cytokine repression via inhibition of NF-kappaB activation in vivo.