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首页> 外文期刊>Journal of endotoxin research >Bacterial endotoxin modifies heat shock factor-1 activity in RAW 264.7 cells: implications for TNF-alpha regulation during exposure to febrile range temperatures.
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Bacterial endotoxin modifies heat shock factor-1 activity in RAW 264.7 cells: implications for TNF-alpha regulation during exposure to febrile range temperatures.

机译：细菌内毒素会改变RAW 264.7细胞中的热休克因子1活性：暴露于高热范围温度期间对TNF-α调节的影响。

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摘要

Recent studies have identified heat shock factor (HSF)-1, the predominant heat/stress-stimulated transcriptional activator of heat shock protein genes as a repressor of certain cytokine genes, including TNF-alpha and IL-1beta. We previously showed that exposing macrophages to febrile-range temperature (FRT; 39.5 degrees C) activates HSF-1 to a DNA binding form that does not activate heat shock protein gene transcription, but apparently represses TNF-alpha and IL-1beta transcription. Prewarming macrophages to 39.5 degrees C for 30 min prior to stimulation with bacterial lipopolysaccharide (LPS) does not change the induction of TNF-alpha transcription, but markedly reduces its duration. This raised the question of how TNF-alpha transcription could occur at all in the presence of activated HSF-1. We used RAW 264.7 cells to test the hypothesis that macrophage activation triggers a transient reversal of HSF-1-mediated repression, thereby allowing induction of TNF-alpha transcription. Electrophoretic mobility shift assays revealed that LPS triggers a transient inactivation of HSF-1 that temporally correlates with TNF-alpha transcription and was associated with a transient increase in HSF-1 molecular weight, a decrease in its pI, and appearance of HSF-1 phosphorylating activity. The serine/threonine phosphatase inhibitor, calyculin A, blocked the inhibitory affect of FRT on LPS-induced TNF-alpha generation and prevented the re-activation of HSF-1. We propose that LPS stimulation of FRT-exposed macrophages stimulates a sequential phosphorylation and dephosphorylation of HSF-1, causing a cycle of inactivation and reactivation of HSF-1 repressor activity that allows a temporally-limited period of gene transcription.
机译：最近的研究已确定热休克因子（HSF）-1是热休克蛋白基因的主要受热/应激刺激的转录激活因子，可作为某些细胞因子基因（包括TNF-alpha和IL-1beta）的阻遏物。我们以前表明巨噬细胞暴露于发热温度（FRT; 39.5摄氏度）激活HSF-1到DNA结合形式不激活热休克蛋白基因转录，但显然抑制TNF-alpha和IL-1beta转录。在用细菌脂多糖（LPS）刺激之前，将巨噬细胞预热至39.5摄氏度，持续30分钟，不会改变TNF-α转录的诱导作用，但会显着缩短其持续时间。这就提出了一个问题，即在激活的HSF-1存在下，TNF-α转录怎么可能发生。我们使用RAW 264.7细胞来测试以下假设：巨噬细胞激活会触发HSF-1介导的阻抑的短暂逆转，从而诱导TNF-α转录。电泳迁移率变动分析表明，LPS会触发HSF-1的瞬时失活，该失活与TNF-alpha转录在时间上相关，并且与HSF-1分子量的瞬时增加，pI的降低以及HSF-1磷酸化的出现有关活动。丝氨酸/苏氨酸磷酸酶抑制剂calyculin A阻止了FRT对LPS诱导的TNF-α产生的抑制作用，并阻止了HSF-1的重新激活。我们建议，LPS刺激FRT暴露的巨噬细胞刺激HSF-1的顺序磷酸化和去磷酸化，从而导致HSF-1阻遏物活性的失活和再激活的循环，从而允许基因转录在时间上受到限制。

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