Novel signal transduction pathway utilized by extracellular HSP70 -: Role of Toll-like receptor (TLR) 2 AND TLR4
Novel signal transduction pathway utilized by extracellular HSP70 -: Role of Toll-like receptor (TLR) 2 AND TLR4
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DOI：
10.1074/jbc.m200497200
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发表时间：
2002-04-26
影响因子：
4.8
通讯作者：
Calderwood, SK
中科院分区：
文献类型：
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作者：
Asea, A;Rehli, M;Calderwood, SK
最近的研究已经开始了对热休克蛋白（HSP）功能的理解的范式转变。现在很清楚，HSP可以并且确实离开哺乳动物细胞，与免疫系统的细胞相互作用，并发挥免疫调节作用。我们最近证明，外源性添加的HSP 70具有强大的细胞因子活性，具有与质膜高亲和力结合的能力，引发快速的细胞内Ca 2+通量，激活NF-κ B，并上调人单核细胞中促炎细胞因子的表达。在这里，我们第一次报告，热休克蛋白70诱导的促炎细胞因子的产生是通过MyD 88/IRAK/NF-κ B信号转导途径介导的，热休克蛋白70利用TLR 2（革兰氏阳性菌受体）和TLR 4（革兰氏阴性菌受体），以CD 14依赖的方式抑制其促炎信号。这些研究现在为开发高效的药理学或分子工具铺平了道路，这些工具将上调或抑制HSP 70诱导的功能，在HSP 70作用理想的情况下（癌症）或HSP 70作用不理想的疾病（关节炎和动脉硬化）。
Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca2+ flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).