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The heat shock paradox: does NF-B determine cell fate?

SUSAN. L. DeMEESTER^*,1, TIMOTHY G. BUCHMAN^*, and J. PERREN COBB^*2

Cellular Injury and Adaptation Laboratory,
^* Departments of Surgery,
Anesthesiology, and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA

²Correspondence: Department of Surgery, Campus Box 8109, 660 South Euclid Ave., St. Louis, MO, 63110, USA. E-mail: cobb{at}msnotes.wustl.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
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-B paradox’) and hypothesize that the mechanism is linked to the downstream effects of induction of NF-B’s endogenous inhibitor, IB, a putative heat shock protein.—DeMeester, S. L., Buchman, T. G., Cobb, J. P. The heat shock paradox: does NF-B determine cell fate?

Key Words: injury • cell death • apoptosis • IB

	INTRODUCTION

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
INJURED PATIENTS MAY sustain diverse stresses subsequent to the initiating insult including shock, fever, surgery, infection, and malnutrition. Although each stress may culminate independently in organ dysfunction and death, a recent description of a ‘two-hit’ paradigm (1) suggests that cellular and organ dysfunction is more likely to occur after sequences of stress. These data suggest that consequences of stress are not merely additive, but rather interact to cause dysfunction (2) . The interactions are not predictable and, what is important, sequence permutations can have opposite effects (3) . Our overarching hypothesis is that stress responses interactions contribute to the fate of cells, tissues, and organisms and that modulation of these interactions have the potential to alter both function and survival. This paper provides an interpretive overview of data identifying important interactions between two prototypic cellular stress responses (the heat shock and inflammatory stress responses), the paradoxical effects of these interactions on cell fate, and our hypothesis that these responses interact to alter outcome at the level of gene transcription.

	STRESS RESPONSE INTERACTIONS ARE IMPLICATED IN CELLULAR AND ORGAN DYSFUNCTION

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
The traditional ‘single-hit’ model for the study of injury incompletely reproduces the complex clinical course of injured hosts, including patients. Recently, a more relevant experimental paradigm based on the ‘two-hit’ hypothesis has been promulgated (1 , 4) . This hypothesis, which is based on the observation that the outcome after stimuli in sequence is distinct from the outcome after each stimulus individually, has also been used successfully to study such diverse clinical entities as cancer, tuberous sclerosis, and polycystic kidney disease. Relative to injury, the two-hit hypothesis of organ failure is diagrammed in Fig. 1 .

View larger version (19K): [in this window] [in a new window]   Figure 1. ‘Two-hit’ paradigm. Two otherwise tolerable stimuli can interact to produce organ failure and death.

Recent investigations indicate that sequences of stressful stimuli produce unexpected phenotypes not only at the organism, but also at the cellular level. More important, these stress stimuli can be sequenced to either cause or prevent dysfunction at both cellular (3 , 5 6 7 8) and organism levels (9 10 11) . It follows from these data that the interaction of cellular stress responses can be used not only to explain, but also potentially to attenuate (treat) injury-induced cellular and organ dysfunction (2) .

	STRESS RESPONSE INTERACTIONS: THE HEAT SHOCK PARADOX

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
Reports from our laboratories and those of others attest to the exciting potential of this line of investigation, particularly as it relates to the adaptive response of cells and animals to heat shock (refer to recent reviews for more details: 12 , 13 ). For example, several groups have shown that deliberate induction of the heat shock response, the most prototypic and conserved of all stress responses, can exert powerful cytoprotective effects against subsequent stress, including those that precipitate death of the cell (programmed type of death or apoptosis) (5 , 7) and death of the host (9 , 11) . In contrast, we and others also found that induction of the heat shock response in cells previously ‘primed’ by lipopolysaccharide (LPS, endotoxin) accelerated cell death by apoptosis (3) . In short, inflammation, followed by heat shock, induced death by apoptosis, but heat shock followed by inflammation induced cytoprotection in our porcine endothelial cell model. Others have corroborated these findings in enterocytes (7) . We concluded that the phenotypic response of cells to heat shock is critically linked to the state of the cell—whether it is in a basal as opposed to an activated (primed) state (2) . We term these seeming paradoxical effects of heat shock on cell fate ‘the heat shock paradox’ (Fig. 2 ). How can the same stimulus (heat shock) be both cytoprotective and cytotoxic? What is the molecular mechanism?

View larger version (19K): [in this window] [in a new window]   Figure 2. Stress-response interactions: the heat shock and NF-B paradoxes.

	ANOTHER PARADOX? INHIBITION OF NF-B DNA BINDING ACTIVITY

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
The molecular basis, tissue and species specificity, and clinical relevance of the heat shock paradox are not known and remain a primary focus of our laboratory. We previously reported that cell fate in our endothelial cell model was dependent on an interaction between induction of programs of gene expression, namely, the inflammatory and heat shock stress responses (2 , 3) . Our recent studies suggest that one facet of this important interaction can be resolved further to the level of gene transcription (14) . This series of investigations began as a focused exploration of LPS ‘priming’ based on the observation that activation of endothelial cells was dependent on activation of the prototypic acute-phase transcription factor nuclear factor kappa B (NF-B), using pyrrolidine dithiocarbamate (PDTC) as an NF-B inhibitor (15) . We subsequently confirmed in our endothelial cell model that PDTC not only inhibited NF-B DNA binding, but had paradoxical effects on endothelial cell fate that were indistinguishable from heat shock (14) . Moreover, PDTC induced heat shock protein 72 (HSP-72) and nuclear translocation of the transcription factor heat shock factor 1 (HSF-1), consistent with induction of the heat shock response (14) .

These data and our review of the literature suggested another paradox, which is that inhibition of NF-B binding activity, like heat shock, could be both cytoprotective (16 , 17) and cytotoxic in a variety of cell types (18) (what we call ‘the NF-B paradox’). In short, we observed that this paradox was strikingly similar to the sequence-specific nature of the heat shock paradox (Fig. 2) . We wondered whether there was overlap at the molecular level between these two paradoxes.

	MECHANISTIC STUDIES: HEAT SHOCK INHIBITS NF-B DNA BINDING ACTIVITY AND INDUCES IB

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
We therefore tested the reciprocal hypothesis that induction of the heat shock response resulted in inhibition of NF-B DNA binding activity. Our findings indicated that induction of the heat shock response inhibited NF-B DNA binding and was associated with accumulation of the endogenous inhibitor of NF-B activity, IB (5) . Specifically, our findings linked increased HSF-1 DNA binding activity with simultaneous inhibition of the binding activity of NF-B, both before and after LPS priming (Fig. 3 ) (5 , 19) . This in turn suggested a mechanism linking induction of the heat shock response with inhibition of NF-B DNA binding via induction of IB, a putative novel heat shock protein (5 , 20) . This hypothesis was simultaneously and independently corroborated by another group of investigators, who not only showed that heat shock increased IB gene transcription in a lung adenocarcinoma cell line, but also identified a potential heat shock-responsive element in the human IB promoter (20) . Together, these data suggest that IB may be a point of interaction between the heat shock and inflammatory stress responses, as well as a mechanistic link between our two paradoxes. Thus, the heat shock paradox, via induction of IB, may be a manifestation of the NF-B paradox.

View larger version (33K): [in this window] [in a new window]   Figure 3. A variety of both thermal and nonthermal agents induce the prototypic heat shock protein (HSP)-72 via activation of the transcription factor heat shock factor 1 (HSF-1). Increased heat shock factor DNA binding activity is associated with inhibition of the binding activity of NF-B in our porcine aortic endothelial cell model. The methods used have been described previously (5 , 14 , 19) . As seen in the Western immunoblot (A), treatment with sodium arsenite (As), authentic heat, and pyrrolidine dithiocarbamate (PDTC) increased HSP-72 protein accumulation compared to controls. B) An electromobility shift assay (EMSA) documenting time-dependent increased HSF-1 translocation to the nucleus of endothelial cells treated with PDTC, a novel inducer of the heat shock response (5) . Lane 1 contained only HSF-1-specific oligonucleotide probe, lane 2 probe plus nuclear extracts from untreated cells, and lanes 3–6 probe plus extracts from PDTC-treated cells (cold competitive inhibitor also was added to lane 4). C) An EMSA showing that agents that induce nuclear translocation of HSF-1, such as PDTC (B) and sodium arsenite, also inhibit nuclear translocation of NF-B stimulated by LPS both before and after treatment with the agent (lanes 6 and 8, respectively). Lane 1 contained only NF-B-specific oligonucleotide probe, lane 2 probe plus nuclear extracts from untreated cells, lanes 3–8 probe plus extracts from LPS-treated cells (cold competitive inhibitor was added to lane 4 and cold noncompetitive inhibitor was added to lane 5).

	DOES NF-B DETERMINE CELL FATE?

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
We have linked heat shock-induced increases in IB activity with paradoxical changes in cell fate by a mechanism associated with decreased NF-B DNA binding activity. If this is true, then (restating our original question), how can the same stimulus—decreased NF-B DNA binding activity—be both cytoprotective and cytotoxic? And again, what is the mechanism?

Significant progress has recently been made as to why inhibiting NF-B DNA binding activity can induce cytotoxicity (apoptosis) in primed cells. In a series of studies (18 , 21 , 22) , three groups independently reported that inhibition of NF-B activity increased apoptosis in cells primed by an inflammatory stimulus [tumor necrosis factor alpha (TNF-)] or ionizing radiation. In addition, targeted disruption of the rel A (p65) subunit of NF-B led to embryonic lethality in mice (23) . Together, these studies suggested that NF-B played a key role as a survival factor, responsible in part for ‘turning on’ genes that could block cell death by apoptosis (24) . Several candidate genes have subsequently been identified. For example, NF-B induces transcription of the inhibitor-of-apoptosis proteins (c-IAP1 and c-IAP2) and the TNF- receptor 1 (TNFR1) signaling proteins TRAF1 and TRAF2 (25) . These four proteins act synergistically to inhibit the cascade of enzymes (caspases) responsible for apoptosis (25) . Thus, we propose that the cytotoxic effect of heat shock stems from induction of IB, which results in decreased NF-B DNA binding and subsequent decreased transcription of antiapoptosis genes, possibly including c-IAP1, c-IAP2, TRAF1, TRAF2, A20 (26) , Bcl-2, and Bcl-X_L (see Fig. 4 ).

View larger version (105K): [in this window] [in a new window]   Figure 4. We hypothesize that the heat shock and inflammatory stress responses intersect at the level of the nucleus: the stress response interaction occurs at the level of the gene transcription. 1. Inflammatory mediators such as LPS simultaneously induce both proapoptotic (caspase 8) and antiapoptotic (IB kinase [IKK]) pathways. 2. Phosphorylation of IB results in release of cytoplasmic NF-B. 3. NF-B translocates from the cytoplasm to the nucleus and binds to the promoters of inflammatory genes. 4. This results in increased transcription and translation of a number of proinflammatory and antiapoptotic genes. 5. Antiapoptotic genes inhibit proapoptotic pathways. 6. Induction of the heat shock response similarly leads to translocation of HSF-1 to the nucleus with resultant transcription and translation of heat shock proteins, including IB. 7. Increased IB decreases NF-B translocation. 8. Decreased NF-B nuclear translocation decreases translation of antiapoptotic proteins. 9. The balance of pro-and antiapoptotic pathways shifts favoring proapoptotic pathways and DNA fragmentation.

On the basis of the studies discussed above, NFB is usually regarded as a survival factor. However, several reports, including our own, document that inhibition of NF-B DNA binding activity can be cytoprotective (5 , 16 , 17) , Careful review indicates that the effect of NF-B inhibition in these reports is critically dependent on NF-B inhibition before cell stress, consistent with our hypothesis. The mechanism by which decreased NF-B affords such cytoprotection is not clear. We have used a variety of mechanistically distinct NF-B inhibitors, including arsenite (5) , PDTC (14) , and nitric oxide (NO) (27) , all of which protected against a subsequent apoptosis-inducing stimulus (LPS/arsenite). We have also reported, however, that PDTC (14) , like arsenite, induces the heat shock response (14) . This raises the possibility that the protective effects of these agents are not caused by altered NF-B DNA binding activity, but rather by the induction of protective heat shock proteins. The cytoprotective effect of heat shock has been linked to increased expression of heat shock proteins (9) , which is dependent on inducible binding to DNA of the transcription activator HSF-1 (28) . In our in vitro model, we were unable to discriminate between induction of HSPs vs. decreased NF-B DNA binding as the mechanism responsible for heat shock-induced cytoprotection (5) . Other NF-B inhibiting stimuli that afford protection, however, do not appear to induce the heat shock response such as dexamethasone and, in our hands, NO (29) .

Other mechanistic explanations are certainly possible, however, and are being explored. It is critical to identify which facet of the heat shock response is responsible for its cytoprotective effect prior to injury and, similarly, which facet is responsible for its cytotoxic effect after injury. For example, it may be that the heat shock paradox is not related to induction of IB and decreased NF-B activity (the NF-B paradox), but to other heat shock-induced cellular changes. These could include increased HSF-1 transcription factor activity, expression of cytoprotective heat shock proteins other than IB [such as HSP-72, HSP-90, and HSP 32 (heme oxygenase)], nonspecific effects such as decreased expression of critical proteins as a result of decreased protein synthesis (30) , or changes in the filamentous cytoskeleton (31) . Answers to these mechanistic questions will also help to determine the importance of decreased NF-B activity per se to cell fate.

	SIGNIFICANCE

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 
At the cellular level, there is substantial potential overlap between stress responses (oxidative, heat, inflammatory, radiation, nitrosative, etc.), but our understanding is poor regarding the nature, degree, and molecular mechanisms by which these interactions occur (2) . Our data and those of others suggest that activation of heat stress responses by fever, ischemia/reperfusion, or caloric restriction after injury may contribute to programmed cell death by apoptosis in activated cells (2 , 3) . On the other hand, induction of the heat shock response prior to injury may offer substantial protection against subsequent stress. The roles of the heat shock and NF-B paradoxes have not been characterized in intact organs nor has their importance been demonstrated in whole animals. In fact, an appreciation of the clinical relevance of the heat shock and NF-B paradoxes is imperative, as laboratories in various disciplines are now testing cytoprotection via induction of the heat shock response or inhibition of NF-B DNA binding activity in preclinical studies. Our data suggest that untimely activation of these responses in cells or animals previously exposed to endotoxin could unexpectedly increase cell death and potentially worsen the outcome (2 , 5) . This argument is strengthened further by our recent reports that organ failure and death in both animals (32) and patients (33) are accompanied by increased stress-induced cell death by apoptosis. Clearly a more detailed mechanistic understanding is needed of the complex interactions of the heat shock and inflammatory stress responses, particularly in light of the issues raised by the overwhelmingly negative results of recent therapeutic trials in patients with sepsis (34) .

	ACKNOWLEDGMENTS

 
The authors gratefully acknowledge the technical contributions of Ms. Yuyu Qiu. The support and guidance provided by Drs. Richard S. Hotckiss and Irene Karl were invaluable to the success of these investigations. This paper was presented in part at The Twentieth Annual Conference on Shock (Indian Wells, California, 1997; ref 19 ) and was supported in part by grants from the American College of Surgeons (S.L.D.), American Association for the Surgery of Trauma (J.P.C.), the Society of Critical Care Medicine (J.P.C.), and NIH GM 59960 (J.P.C.).

	FOOTNOTES

 
¹ Current address: Tower 110, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD 21287, USA.

Received for publication May 26, 2000. Accepted for publication June 29, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION STRESS RESPONSE INTERACTIONS ARE... STRESS RESPONSE INTERACTIONS:... ANOTHER PARADOX? INHIBITION OF... MECHANISTIC STUDIES: HEAT SHOCK... DOES NF-{kappa}B DETERMINE CELL... SIGNIFICANCE REFERENCES

 

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