Hypothermia enhances phosphorylation of IκB kinase and prolongs nuclear localization of NF-κB in lipopolysaccharide-activated macrophages
Hypothermia enhances phosphorylation of IκB kinase and prolongs nuclear localization of NF-κB in lipopolysaccharide-activated macrophages
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DOI：
10.1152/ajpcell.00152.2005
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发表时间：
2005-11-01
影响因子：
5.5
通讯作者：
Hasday, JD
中科院分区：
文献类型：
--
作者：
Fairchild, KD;Singh, IS;Hasday, JD
低温（HT）在各种病理生理状态下都与有益和有害的后果有关。虽然HT通常被认为具有抗炎和细胞保护作用，但我们之前已经表明，适度的体外HT延长了lps刺激的单核吞噬细胞产生tnf - α的时间，部分原因是延长了tnf - α基因的转录和多效性转录因子NF-kappa b的激活。我们进一步表征了中度（32℃）和显著（28℃）高温对人单核THP-1细胞的影响，表明即使短时间（2小时）暴露于高温下，然后回到常温条件下22小时，也会导致tnf - α的产生增加和延长。在这些研究中，热休克蛋白72的产生和热休克因子1的激活不受高温的影响，这表明这种影响不是广义应激反应的一部分。利用免疫印迹法，我们已经证明高温增强了ikk - β和ikk - α的磷酸化（28℃时增加8倍，32℃时增加3.6倍，而37℃时增加3.6倍）。此外，NF-kappa B p65的核积累在低温细胞中显著延长（28℃下2和4 h时核p65比37℃时多1.4倍和2.5倍）。在ht暴露的细胞中，有助于nf - κ b依赖性转录终止的I κ b - α的再表达延迟了数小时。因此，我们已经表明，临床相关的HT改变了负责nf - κ B激活和失活的细胞质和核事件。增强的nf - κ B激活可能有助于HT在各种临床环境中的免疫调节作用。
Hypothermia (HT) has been associated with both beneficial and detrimental consequences in various pathophysiological states. While HT is generally thought to have anti-inflammatory and cytoprotective effects, we have previously shown that moderate in vitro HT prolongs TNF-alpha production by LPS-stimulated mononuclear phagocytes, in part by prolonging TNF-alpha gene transcription and activation of the pleiotropic transcription factor NF-kappa B. In this study, we have further characterized the effect of moderate (32 degrees C) and marked (28 degrees C) HT in human monocytic THP-1 cells by showing that even short (2 h) exposure to HT followed by a return to normothermic conditions for 22 h resulted in augmented and prolonged production of TNF-alpha. Production of heat shock protein 72 and activation of heat shock factor 1 are not affected by HT in these studies, suggesting that the effect is not part of a generalized stress response. Using immunoblotting, we have shown that HT augments phosphorylation of IKK-beta and IKK-alpha (up to an 8-fold increase at 28 degrees C and a 3.6- fold increase at 32 degrees C vs. 37 degrees C). Furthermore, nuclear accumulation of NF-kappa B p65 was significantly prolonged in hypothermic cells (1.4- and 2.5- fold more nuclear p65 at 2 and 4 h at 28 vs. 37 degrees C). Reexpression of I kappa B-alpha, which contributes to the termination of NF-kappa B-dependent transcription, was delayed several hours in HT-exposed cells. Thus we have shown that clinically relevant HT alters both cytosolic and nuclear events responsible for NF-kappa B activation and deactivation. Enhanced NF-kappa B activation may contribute to the immunomodulatory effects of HT in various clinical settings.