The heat shock paradox: does NF-kappaB determine cell fate?
Cellular injury induces an adaptive response whether the insult is physical (e.g., heat, radiation), chemical (e.g., reactive oxygen species), infectious (e.g., bacteria), or inflammatory (e.g., lipopolysaccharide). Recent data indicate that the interactions of these responses are not predictable and that sequence permutations can have opposite effects on outcome after injury. Our overarching hypothesis is that interactions among stress responses contribute to the fate of cells, tissues, and organisms and that modulation of these interactions can have important affects on both function and survival. For example, whereas it is well known that a prior heat shock stress can protect cells against inflammatory stress both in vitro and in vivo, we and others have shown that induction of a subsequent heat stress in cells 'primed' by inflammation can precipitate cell death by apoptosis. We call this seemingly paradoxical ability of heat shock to induce cytoprotection and cytotoxicity the heat shock paradox. The molecular mechanisms by which cells integrate responses to these and other stresses are poorly understood. We present data linking the heat shock paradox to the activity of the acute-phase transcription factor nuclear factor kappa B (identifying an 'NF-kappaB paradox') and hypothesize that the mechanism is linked to the downstream effects of induction of NF-kappaB's endogenous inhibitor, IkappaBalpha, a putative heat shock protein.
DeMeester
S L
SL
Cellular Injury and Adaptation Laboratory, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Buchman
T G
TG
Cobb
J P
JP
D000210:Acute-Phase Reaction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D019610:Cytoprotection; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology*; D006358:Hot Temperature; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D013312:Stress, Physiological / Q000378:metabolism / Q000473:pathology
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA