Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype
Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype
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DOI：
10.4049/jimmunol.170.5.2340
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发表时间：
2003-03-01
影响因子：
4.4
通讯作者：
Kolb, H
中科院分区：
文献类型：
--
作者：
Flohé, SB;Brüggemann, J;Kolb, H
热休克蛋白（HSP）60非特异性激活先天免疫系统的细胞。在本研究中，我们的特点是人热休克蛋白60的成熟，细胞因子的释放，和T细胞活化能力的骨髓来源的树突状细胞（DC）的影响。此外，我们分析了HSP 60诱导的DC信号转导。HSP 60强烈刺激DC成熟和释放TNF-α、IL-12和IL-1 β。然而，HSP 60仅引起DC中弱的IL-10应答，表明Th 1偏好。HSP 60处理的DC诱导同种异体T细胞增殖。同样，Th 1偏好被注意到，同种异体T细胞和HSP 60处理的DC的共培养物释放IFN-γ，但仅释放少量IL-10，并且没有可检测的IL-4。通过Toll样受体4的信号转导参与了HSP 60诱导的细胞因子释放和成熟，因为具有突变Toll样受体4的C3 H/HeJ小鼠的DC显示出对HSP 60的反应不足。HSP 60可迅速激活DC中的丝裂原活化蛋白激酶p38、c-Jun N-末端激酶、细胞外信号调节激酶以及IkappaB。这些信号分子的磷酸化也由LPS介导，但具有慢得多的动力学。因此，HSP 60比LIPS更快地刺激DC，并产生Th 1促进表型。这些结果表明，DC发挥了关键作用，在启动破坏性的Th 1型反应在网站的局部HSP 60的释放。
Heat shock protein (HSP) 60 nonspecifically activates cells of the innate immune system. In the present study, we characterized the effects of human HSP60 maturation, cytokine release, and T cell-activating capacity of bone marrow-derived dendritic cells (DC). Furthermore, we analyzed HSP60-induced signal transduction in DC. HSP60 strongly stimulated DC for maturation and release of TNF-alpha, IL-12, and IL-1beta. However, HSP60 elicited only a weak IL-10 response in DC suggesting a Th1 bias. HSP60-treated DC induced proliferation of allogeneic T cells. Again, a Th1 bias was noted in that cocultures of allogeneic T cells and HSP60-treated DC released IFN-gamma but only small amounts of IL-10 and no detectable IL-4. Signaling via Toll-like receptor 4 was involved in HSP60-induced cytokine release and maturation because DC of C3H/HeJ mice with a mutant Toll-like receptor 4 showed deficient response to HSP60. HSP60 was found to rapidly activate the mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase as well as IkappaB in DC. Phosphorylation of these signaling molecules was also mediated by LPS, but with much slower kinetics. Thus, HSP60 stimulates DC more rapidly than LIPS and elicits a Th1-promoting phenotype. These results suggest that DC play a pivotal role in priming for destructive Th1-type responses at sites of local HSP60 release.