TNFα mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response
TNFα mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response
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DOI：
10.1038/sj.cdd.4401276
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发表时间：
2003-10-01
影响因子：
12.4
通讯作者：
Steiner, G
中科院分区：
文献类型：
--
作者：
Schett, G;Steiner, CW;Steiner, G
肿瘤坏死因子α独一无二地将促炎症特征与促凋亡潜力结合在一起。HSF1的激活和HSP70的诱导是应激反应的一部分，它保护细胞免受凋亡。在此，我们研究了肿瘤坏死因子α对热休克蛋白70应激反应的影响。肿瘤坏死因子α引起HSF1激活和HSP70合成的一过性下调，导致对热诱导的细胞凋亡的敏感性增加。阻断肿瘤坏死因子-R1，但不阻断肿瘤坏死因子-R2，以及抑制蛋白磷酸酶PP1/PP2a和PP2b，可完全阻断这一作用。相反，阻断MAPK/SAPK-、NF-kappaB和PKC-通路以及caspase级联并不能阻止HSF1/HSP70的下调。这些数据表明，肿瘤坏死因子α通过肿瘤坏死因子-R1和蛋白磷酸酶的激活来暂时抑制HSP70应激反应。抑制基本的细胞应激反应的代价是增加对凋亡细胞死亡的敏感性。
TNFalpha uniquely combines proinflammatory features with a proapoptotic potential. Activation of HSF1 followed by induction of hsp70 is part of a stress response, which protects cells from apoptosis. Herein, the effects of TNFalpha on the hsp70 stress response were investigated. TNFalpha caused transient downregulation of HSF1 activation and hsp70 synthesis, leading to increased sensitivity to heat-induced apoptosis. Blockade of TNF-R1, but not TNF-R2, as well as inhibition of protein phosphatases PP1/PP2a and PP2b completely blocked this effect. In contrast, blockade of MAPK/SAPK-, NF-kappaB (NF-kappaB)-, and PKC- pathways as well as the caspase cascade did not prevent downregulation of HSF1/hsp70. These data demonstrate that TNFalpha transiently inhibits the hsp70 stress response via TNF-R1 and activation of protein phosphatases. The price of inhibition of an essential cellular stress response is increased sensitivity to apoptotic cell death.