Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1)

Murapa, Patience; Gandhapudi, Siva K.; Skaggs, Hollie S.; Sarge, Kevin D.; Woodward, Jerold G.

doi:10.4049/jimmunol.179.12.8305

Cited by 30 publications

(48 citation statements)

References 57 publications

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“…Partial activation of HSF1 has been described during exposure to febrile, sub-heat shock temperatures [28], [29], [30], [31]. To investigate whether COX-2 expression may be induced at febrile temperatures in endothelial cells, HUVECs were either kept at 37°C or were incubated at 40 and 41°C for 8 hours.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

et al. 2012

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The heat-shock response, a fundamental defense mechanism against proteotoxic stress, is regulated by a family of heat-shock transcription factors (HSF). In humans HSF1 is considered the central regulator of heat-induced transcriptional responses. The main targets for HSF1 are specific promoter elements (HSE) located upstream of heat-shock genes encoding cytoprotective heat-shock proteins (HSP) with chaperone function. In addition to its cytoprotective function, HSF1 was recently hypothesized to play a more complex role, regulating the expression of non-HSP genes; however, the non-canonical role of HSF1 is still poorly understood. Herein we report that heat-stress promotes the expression of cyclooxygenase-2 (COX-2), a key regulator of inflammation controlling prostanoid and thromboxane synthesis, resulting in the production of high levels of prostaglandin-E2 in human cells. We show that heat-induced COX-2 expression is regulated at the transcriptional level via HSF1-mediated signaling and identify, by in-vitro reporter gene activity assay and deletion-mutant constructs analysis, the COX-2 heat-responsive promoter region and a new distal cis-acting HSE located at position −2495 from the transcription start site. As shown by ChIP analysis, HSF1 is recruited to the COX-2 promoter rapidly after heat treatment; by using shRNA-mediated HSF1 suppression and HSE-deletion from the COX-2 promoter, we demonstrate that HSF1 plays a central role in the transcriptional control of COX-2 by heat. Finally, COX-2 transcription is also induced at febrile temperatures in endothelial cells, suggesting that HSF1-dependent COX-2 expression could contribute to increasing blood prostaglandin levels during fever. The results identify COX-2 as a human non-classical heat-responsive gene, unveiling a new aspect of HSF1 function.

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Section: Resultsmentioning

confidence: 99%

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

et al. 2012

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“…CD8 ؉ T cell activation is not impaired in HSF1-deficient mice. We previously showed that HSF1-deficient T cells incubated at an elevated temperature (39.5°C) had an impaired ability to proliferate in response to anti-CD3/CD28 stimulation in vitro compared with T cells isolated from HSF1 ϩ/ϩ mice (26). Given these results, we predicted that L. monocytogenesinfected HSF1-deficient mice might have a decreased CD8 ϩ T cell response because of the fever induced during the first few days of infection.…”

Section: Monocytogenes Infection Triggers An Increase In Core Bodymentioning

confidence: 89%

“…We previously showed that the transcription factor HSF1 was important for protecting T cell function when T cells were incubated at elevated temperatures within the range of a physiological fever response (26). To address the role of HSF1 during bacterial infection, we chose to study L. monocytogenes, since clearance of this intracellular bacterial pathogen is known to be strictly dependent on T cells (6,19).…”

Section: Monocytogenes Infection Triggers An Increase In Core Bodymentioning

confidence: 99%

“…In a previous in vitro study, we showed that T cells isolated from HSF1-deficient mice were unable to proliferate efficiently at physiologic fever temperature (39.5°C) (26). To further address this question in vivo, we chose to study the role of HSF1 during Listeria monocytogenes infection, since clearance of this intracellular bacterial pathogen is strictly dependent on protective T cell responses.…”

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confidence: 99%

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Heat Shock Factor 1 Protects Mice from Rapid Death duringListeria monocytogenesInfection by Regulating Expression of Tumor Necrosis Factor Alpha during Fever

et al. 2011

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Heat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42°C). However, we recently showed that HSF1 is activated at a lower temperature (39.5°C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance of Listeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8؉ T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2°C in L. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than did HSF1 ؉/؉ littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1-deficient mice did not show a defect in CD8 ؉ T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses of L. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-␣ enhanced the survival of HSF1-deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens.

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“…Fever-range whole body thermal therapy has been shown to enhance the host immune response, whereas extreme systemic thermal therapy (41.5– 42°C) may impair immune function [14,15]. Fever-range hyperthermia can induce expression of heat shock proteins [16, 17], enhance antigen presentation by dendritic cells [18, 15], promote dendritic cell maturation [18, 14] and activate immune effector cells (T lymphocytes and NK cells) [15, 19, 20]. New studies suggest that fever-like temperatures also activate an innate immune response by promoting toll-like receptor 4 (TLR4) signaling [21].…”

Section: Introductionmentioning

confidence: 99%

Fever-range whole body thermotherapy combined with oxaliplatin: A curative regimen in a pre-clinical breast cancer model

Rowe¹,

Strebel²,

Proett³

et al. 2010

International Journal of Hyperthermia

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Purpose Studies were conducted to test whether fever-range whole body hyperthermia, rationally combined with oxaliplatin chemotherapy, would boost its efficacy without substantial toxicity. Materials and Methods The effect of heat on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumor cell line. In vivo, oxaliplatin was given with thermal therapy to rats bearing highly treatment-resistant MTLn3 mammary adenocarcinomas at various doses and times before, during, and after heating. Tumor growth, survival, and toxicity were measured to determine treatment outcome. Results Heating for 6h at 40°C halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24h before 6h of fever-range thermal therapy were completely, immunologically, cured while a further 11% regressed their primary tumor but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumor efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 hours before FR-WB-TT. Conclusions When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumors in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

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Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1)

Cited by 30 publications

References 57 publications

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells

Heat Shock Factor 1 Protects Mice from Rapid Death duringListeria monocytogenesInfection by Regulating Expression of Tumor Necrosis Factor Alpha during Fever

Fever-range whole body thermotherapy combined with oxaliplatin: A curative regimen in a pre-clinical breast cancer model

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