Differential effects of hyperthermia on macrophage interleukin-6 and tumor necrosis factor-alpha expression

Ensor, J. E.; Wiener, S. M.; McCrea, K. A.; Viscardi, Rose M.; Crawford, Eric K.; Hasday, Jeffrey D.

doi:10.1152/ajpcell.1994.266.4.c967

Cited by 147 publications

(90 citation statements)

References 22 publications

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“…This finding led us to conclude that heat shock inhibits LPSinduced IL-6 expression in mouse cells. Previous reports showed that IL-6 expression was not inhibited by hyperthermia in human macrophages treated with LPS (10) and that hyperthermia promoted IL-6 production in human enterocytes (47). Furthermore, treatment with hyperthermia in mice resulted in an increase in serum IL-6 levels (48).…”

Section: Discussionmentioning

confidence: 95%

“…These beneficial roles of fever are mediated partly by a strengthening of immune surveillance through lymphocyte trafficking (7), as well as by the suppression of pyrogenic and inflammatory cytokines, such as IL-1 and TNF-a, in the cell (8)(9)(10) and body (6,11). However, it is unclear whether hyperthermia inhibits the expression of IL-6 as it affects IL-6 and TNF-a expression differently in macrophages (10).…”

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confidence: 99%

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Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

Takii

Inouye

Fujimoto

et al. 2009

The Journal of Immunology

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The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

Takii

Inouye

Fujimoto

et al. 2009

The Journal of Immunology

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“…Mean Ϯ SE; n ϭ 6; ‫,ء‬ P Ͻ 0.05 compared with the "no fever" mice. (11,12,18). We also reported that increasing core temperature in LPS-challenged mice accelerated and enhanced an early, self-limited pulse of TNF-␣ in plasma but subsequently suppressed persistent TNF-␣ expression and enhanced the expression of IL-6 (17,18).…”

Section: Resultsmentioning

confidence: 99%

Febrile Core Temperature Is Essential for Optimal Host Defense in Bacterial Peritonitis

et al. 2000

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Fever, a nonspecific acute-phase response, has been associated with improved survival and shortened disease duration in infections, but the mechanisms of these beneficial responses are poorly understood. We previously reported that increasing core temperature of bacterial endotoxin (LPS)-challenged mice to the normal febrile range modified expression of tumor necrosis factor alpha (TNF-␣), interleukin 1␤ (IL-1␤), and IL-6, three cytokines critical to mounting an initial defense against microbial pathogens, but survival was not improved in the warmer animals. We speculated that our inability to show a survival benefit of optimized cytokine expression in the warmer animals reflected our use of LPS, a nonreplicating agonist, rather than an infection with viable pathogens. The objective of this study was to determine if increasing murine core temperature altered cytokine expression and improved survival in an experimental bacterial peritonitis model. We showed that housing mice at 35.5°C rather than 23°C increased core temperature from 36.5 to 37.5°C to 39.2 to 39.7°C, suppressed plasma TNF-␣ expression for the initial 48 h, delayed gamma interferon expression, improved survival, and reduced the bacterial load in mice infected with Klebsiella pneumoniae peritonitis. We showed that the reduced bacterial load was not caused by a direct effect on bacterial proliferation and probably reflected enhanced host defense. These data suggest that the increase in core temperature that occurs during bacterial infections is essential for optimal antimicrobial host defense.

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“…It is well documented that HSP induction within the cell can downregulate the inflammatory cascade by reducing TNF-␣ production to inflammatory stimuli (11,18,36,73,79). The mechanism responsible for the upregulation of HSP during inflammatory stimuli results from serine kinase and mitogen-activated protein kinase (MAPK) activation of the NF-B pathway, coupled with the production of reactive oxygen species and subsequent oxidative stress in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals

Selkirk¹,

McLellan²,

Wright³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Selkirk GA, McLellan TM, Wright HE, Rhind SG. Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals. Am J Physiol Regul Integr Comp Physiol 296: R575-R586, 2009. First published January 21, 2009 doi:10.1152/ajpregu.90683.2008.-This study examined intracellular cytokine, heat shock protein (HSP) 72, and cellular apoptosis in classic and inflammatory CD14 ϩ monocyte subsets during exertional heat stress (EHS). Subjects were divided into endurance-trained [TR; n ϭ 12, peak aerobic power (V O2peak) ϭ 70 Ϯ 2 ml⅐ kg lean body mass (LBM) Ϫ1 ⅐ min Ϫ1 ] and sedentary-untrained (UT; n ϭ 11, V O2peak ϭ 50 Ϯ 1 ml⅐ kg LBM Ϫ1 ⅐ min Ϫ1 ) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40°C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5°C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0°C/Exh) were analyzed for cytokines (TNF-␣, IL-1␤, IL-6, IL-1ra, and IL-10) in CD14 ϩϩ CD16 Ϫ /CD14 ϩ CD16 ϩ and HSP72/apoptosis in CD14 Bri / CD14 Dim subsets. In addition, serum levels of extracellular (e)HSP72 were also examined. Baseline and Exh samples were separately stimulated with LPS (1 g/ml) or heat shocked (42°C) and cultured in vitro for 2 h. A greater temperature-dependent increase in CD14 ϩ CD16 ϩ cells was observed in TR compared with UT subjects as well as a greater LPS tolerance following in vitro LPS stimulation. TNF-␣ and IL-1␤ cytokine expression was elevated in CD14 ϩ CD16 ϩ but not in CD14 ϩϩ CD16 Ϫ cells. A greater induction of intracellular HSP72 and eHSP72 was observed in TR compared with UT subjects, which coincided with reduced apoptosis at Exh and following in vitro heat shock. Induced HSP in vitro was not uniform across CD14 ϩ subsets. Findings suggest that circulating CD14 ϩ CD16 ϩ , but not CD14 ϩϩ CD16 Ϫ monocytes, contribute to the proinflammatory cytokine profiles observed during EHS. In addition, the enhanced HSP72 response in endurance-trained individuals may confer improved heat tolerance through both anti-inflammatory and anti-apoptotic mechanisms. immune function; cardiovascular/thermoregulatory strain; flow cytometry; heat shock protein PERIPHERAL BLOOD MONOCYTES play an important role in protection against invading pathogens and activation of innate immunity (46). Based on differential expression of antigenic markers CD14 [part of the LPS receptor, CD14/Toll-like receptor (TLR-4)/MD-2] and CD16 (Fc␥RIII), monocytes can be divided into two phenotypically and functionally distinct subsets (82, 90). The bulk of monocytes are defined as classic monocytes and are strongly positive for surface receptor CD14 (CD14 ϩϩ CD16 Ϫ ), whereas the minor subset are referred to as inflammatory monocytes (CD14 ϩ CD16 ϩ ) because of their high capacity to express proinflammatory cytokines such as TNF-␣ (6, 62, 64, 90). Inflammatory monocytes have the ability to respond directly with antimicrobial activity, whereas the clas...

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Differential effects of hyperthermia on macrophage interleukin-6 and tumor necrosis factor-alpha expression

Cited by 147 publications

References 22 publications

Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

Febrile Core Temperature Is Essential for Optimal Host Defense in Bacterial Peritonitis

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals

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