TNFa 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 TNFa on the hsp70 stress response were investigated. TNFa 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-jB (NF-kappaB)-, and PKC-pathways as well as the caspase cascade did not prevent downregulation of HSF1/hsp70. These data demonstrate that TNFa 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.