The Heat Shock Response

The heat shock response is another fundamental endogenous cytoprotective mechanism found in virtually all organisms [52-55], Originally described in Drosophila [56], it is now known to occur throughout the animal kingdom from prokaryotes through humans. The heat shock response is defined by the rapid expression of a class of proteins known as heat shock proteins, when a cell, tissue, or intact organism is exposed to elevated temperatures. In addition, heat shock proteins can be induced by a wide variety of non-thermal stressors and pharmacological agents (Table I).

One functional significance of the heat shock response, whether induced by thermal or nonthermal stress, is that it confers protection against subsequent and otherwise lethal hyperthermia; a phenomenon referred to as thermotolerance [57,58]. Perhaps more interesting from a clinical standpoint is the phenomenon of cross-tolerance, whereby induction of the heat shock response confers protection against non-thermal cytotoxic stimuli. For example, in vitro experiments have demonstrated that induction of the heat shock response protects endothelial cells against endotoxin-mediated apoptosis [59]. Other examples include heat shock response-dependent protection against nitric oxide [60], peroxynitrite [61], and hydrogen peroxide [62]. In vivo, induction of the heat shock response protects animals against endotoxemia/sepsis [63,64], acute

Table I Non-thermal inducers of the heat shock response.

Inducer

Comments

Sodium Arsenite

Prostaglandin-A,

Dexamethasone

Bimoclomol

Herbimycin A

Geldanamycin

Aspirin

Non-steroidal antiinflammatory drugs

Serine Protease Inhibitors

Pyrrolidine Dithiocarbamate

Diethyldithiocarbamate

Glutamine

Heavy Metal Ions

Phosphatase Inhibitors

Curcumin

Geranylgeranlyacetone

Used extensively in vitro and in vivo Other prostaglandins also active Variable effect

Hydroxylamine derivative, non-toxic Tyrosine kinase inhibitor Tyrosine kinase inhibitor and HSP 90 inhibitor Lowers temperature threshold for HSP induction Lowers temperature threshold for HSP induction Concomitant inhibition of NF-kB. Antioxidant; inhibitor of NF-kB Similar to PDTC

May be specific for intestinal epithelium Cadmium, Zinc

Tyrosine and Ser/Thr phosphatases

Major constituent of turmeric; antiinflammatory

Anti-ulcer drug lung injury [65], and ischemia-reperfusion injury [66].

The mechanisms by which the heat shock response confers such broad cytoprotection are not fully understood. Several lines of evidence, however, indicate that heat shock protein 70 (HSP70) plays a central role in cytoprotection. For example, HSP70 is the most highly induced heat shock protein in cells and tissues undergoing the heat shock response [52-55], and is known to be induced in patients with a variety of critical illnesses or injuries [67,68], Microinjection of anti-HSP70 antibody into cells impairs their ability to achieve thermotolerance [69], Increased expression of HSP70 by gene transfer/transfection has been demonstrated to confer protection against in vitro toxicity secondary to lethal hyperthermia [70], endotoxin [59], nitric oxide [60], and hyperoxia [71], and in vivo ischemia-reperfusion injury [72-74], Mice deficient in heat shock factor-1, the transcription factor responsible for high level expression of HSP70, have a drastically reduced ability to express HSP70, and cells from these animals can not be made ther-motolerant and are more susceptible to oxidant stress [75-77], In addition, heat shock factor-1 deficient mice demonstrate an increase in mortality when challenged with systemic endotoxin [76]. Collectively, these data strongly suggest that HSP70 is central to the cytoprotective properties of the heat shock response. The mechanisms by which HSP70 confers protection are not fully understood, but most likely relate to the ability of HSP70, and other heat shock proteins, to serve as molecular chaperones by binding, re-folding, transporting, and stabilizing damaged intracellular proteins [52-55].

Another potential mechanism by which the heat shock response may confer cytoprotection is by modulating inflammatory responses. The heat shock response has been demonstrated to inhibit a number of genes related to inflammation, including tumour necrosis factor-a, interleukin-l(3, inducible nitric oxide synthase, interleukin-8, RANTES, C3, macrophage chemotactic protein-1, and intracellular adhesion molecule-1 [78-85], In addition, it has been postulated that the inhibitory effects of the heat shock response are relatively selective for inflammation-associated genes [86], The mechanisms by which the heat shock response inhibits proinflammatory gene expression involves inhibition of NF-kB. Several in vitro and in vivo studies have demonstrated that induction of the heat shock response inhibits activation of NF-kB, a pluripotent transcription factor that regulates the expression of many genes associated with inflammation [87-91], The latest work in the area has identified IkB kinase (IKK) as the most upstream target through

Table II Genes regulated by HIF-1 (adapted from Ref. [97]).

Adrenomedullin Endothelin-1 Erythropoietin Heme oxygenase-1 Hexokinase 1 and 2 Lactate dehydrogenase A Nitric oxide synthase 2 P35srj

Phosphoglycerate kinase 1 Transferrin

Vascular endothelial growth factor

Aldolase A and C Enolase 1

Glucose transporter 1 and 3 Glyceraldehyde phosphate dehydrogenase Insulin-like growth factor-II Insulin-like growth factor binding protein 1 and 3 p21

Phosphofructokinase L Pyruvate kinase M Transferrin receptor

Vascular endothelial growth factor receptor which the heat shock response modulates NF-kB activity. IKK is the rate limiting step in the activation of NF-kB in that it phosphorylates the endogenous NF-kB inhibitor, IkBoc. Phosphorylation of IicBa leads to its rapid degradation by a ubiquitin/proteasome-dependent mechanism, thus releasing NF-kB to enter the nucleus. Induction of the heat shock response inhibits activation of IKK, in part by an intracellular phosphatase-dependent mechanism [85,92-94]. Inhibition of IKK subsequently inhibits phosphorylation and degradation of IkBoc [95], thus keeping NF-kB in an inactive state. Finally, the heat shock response also leads to de novo expression of IkBoc, thus providing another potential mechanism for inhibiting NF-kB activity [81,89,96].

In summary, the heat shock response serves a very broad cytoprotective role in virtually all organisms. HSP70 and heat shock factor-1 play key roles in cytoprotection and it would appear that anti-inflammatory effects of the heat shock response also play a prominent role in cytoprotection. The challenge remains to devise an effective and safe method (i.e., gene therapy or pharmacology) for inducing the heat shock response as a therapeutic strategy in the clinical setting.

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