Hsp72 induces inflammation and regulates cytokine production in airway epithelium through a TLR4- and NF-κB-Dependent mechanism
Hsp72 induces inflammation and regulates cytokine production in airway epithelium through a TLR4- and NF-κB-Dependent mechanism
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DOI：
10.4049/jimmunol.179.9.6318
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Page, Kristen
中科院分区：
文献类型：
--
作者：
Chase, Margaret A.;Wheeler, Derek S.;Page, Kristen
热休克蛋白通常被认为是作为分子伴侣的细胞内蛋白;然而，Hsp 72也在细胞外室中被检测到。在急性肺损伤患者的支气管肺泡灌洗液（BALF）中发现了热休克蛋白72。为了解决Hsp 72是否直接激活气道上皮，用重组Hsp 72处理人支气管上皮细胞（16 HBE 14 o-）。热休克蛋白72诱导IL-8表达的剂量依赖性增加，这是抑制NF-κ B抑制剂parthenopropyl。热休克蛋白72诱导NF-κ B B的活化，如NF-κ B B的反式活化和p65 RelA和p50 NF-κ B1与DNA的结合所证明的。热休克蛋白72制备物的内毒素污染不是这些效应的原因。然后，BALB/c小鼠用单次气管内吸入Hsp 72进行攻击，并在4 h后处死。热休克蛋白72诱导显着上调KC，TNF-α，中性粒细胞募集，髓过氧化物酶在BALF中。在TLR 4突变小鼠中用Hsp 72进行类似的攻击没有刺激炎症反应，强调了TLR 4在Hsp 72介导的肺部炎症中的重要性。最后，培养的小鼠气管上皮细胞（MTEC）从BALB/c和TLR 4突变和野生型小鼠离体热休克蛋白72治疗。热休克蛋白72诱导的NF-κ B依赖的方式从BALB/c和野生型MTEC的KC表达显着增加，然而，TLR 4突变MTEC有最小的细胞因子释放。综上所述，这些数据表明，热休克蛋白72的释放和生物活性的BALF中，可以调节气道上皮细胞的细胞因子表达的TLR 4和NF-κ B依赖性机制。
Heat shock proteins are generally regarded as intracellular proteins acting as molecular chaperones; however, Hsp72 is also detected in the extracellular compartment. Hsp72 has been identified in the bronchoalveolar lavage fluid (BALF) of patients with acute lung injury. To address whether Hsp72 directly activated airway epithelium, human bronchial epithelial cells (16HBE14o-) were treated with recombinant Hsp72. Hsp72 induced a dose-dependent increase in IL-8 expression, which was inhibited by the NF-kappa B inhibitor parthenolide. Hsp72 induced activation of NF-kappa B, as evidenced by NF-kappa B trans-activation and by p65 RelA and p50 NF-kappa B1 binding to DNA. Endotoxin contamination of the Hsp72 preparation was not responsible for these effects. Next, BALB/c mice were challenged with a single intratracheal inhalation of Hsp72 and killed 4 h later. Hsp72 induced significant up-regulation of KC, TNF-alpha, neutrophil recruitment, and myeloperoxidase in the BALF. A similar challenge with Hsp72 in TLR4 mutant mice did not stimulate the inflammatory response, stressing the importance of TLR4 in Hsp72-mediated lung inflammation. Last, cultured mouse tracheal epithelial cells (MTEC) from BALB/c and TLR4 mutant and wild-type mice were treated ex vivo with Hsp72. Hsp72 induced a significant increase in KC expression from BALB/c and wild-type MTEC in an NF-kappa B-dependent manner; however, TLR4 mutant MTEC had minimal cytokine release. Taken together, these data suggest that Hsp72 is released and biologically active in the BALF and can regulate airway epithelial cell cytokine expression in a TLR4 and NF-kappa B-dependent mechanism.