HSP70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway
HSP70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway
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DOI：
10.1074/jbc.m111204200
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发表时间：
2002-04-26
影响因子：
4.8
通讯作者：
Wagner, H
中科院分区：
文献类型：
--
作者：
Vabulas, RM;Ahmad-Nejad, P;Wagner, H
人热休克蛋白（HSP）70激活先天免疫细胞，因此不需要额外的佐剂来使结合肽具有免疫原性。在这里，我们测试了内源性HSP70激活Toll/IL-1受体信号通路的假设，类似于HSP60和病原体衍生的分子模式。我们发现HSP70在巨噬细胞中诱导白细胞介素-12 （IL-12）和内皮细胞-白细胞粘附分子-1 （ELAM-1）启动子，这是由MyD88和TRAF6控制的。此外，HSP70导致MyD88重新定位，MyD88缺陷的树突状细胞不响应HSP70产生促炎细胞因子。利用toll样受体（TLR）的遗传互补系统，我们发现TLR2和TLR4在293T成纤维细胞中赋予对HSP70的响应性。越来越多的内源性配体能够激活古老的Toll/IL-1受体信号通路，这符合“危险假说”，即先天免疫系统能够感知危险信号，即使它们来自自身。
Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the "danger hypothesis" proposing that the innate immune system senses danger signals even if they originate from self.