TNFalpha mediates susceptibility to heat-induced apoptosis by protein phosphatase-mediated inhibition of the HSF1/hsp70 stress response.
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.
D021581:Active Transport, Cell Nucleus; D017304:Annexin A5 / Q000032:analysis; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism* / Q000494:pharmacology; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology*; D006358:Hot Temperature; D006801:Humans; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
D017304:Annexin A5; D015703:Antigens, CD; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C070389:HSF2 protein, human; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D020169:Caspases