title: Attenuated thermoregulatory, metabolic, and liver acute phase protein response to heat stroke in TNF receptor knockout mice.
abstract: Tumor necrosis factor (TNF) is considered an adverse mediator of heat stroke (HS) based on clinical studies showing high serum levels. However, soluble TNF receptors (sTNFR; TNF antagonists) were higher in survivors than nonsurvivors, and TNFR knockout (KO) mice showed a trend toward increased mortality, suggesting TNF has protective actions for recovery. We delineated TNF actions in HS by comparing thermoregulatory, metabolic, and inflammatory responses between B6129F2 (wild type, WT) and TNFR KO mice. Before heat exposure, TNFR KO mice showed ~0.4°C lower core temperature (T(c); radiotelemetry), ~10% lower metabolic rate (M(r); indirect calorimetry), and reduced plasma interleukin (IL)-1α and sIL-1RI than WT mice. KO mice selected warmer temperatures than WT mice in a gradient but remained hypothermic. In the calorimeter, both genotypes showed a similar heating rate, but TNFR KO maintained lower T(c) and M(r) than WT mice for a given heat exposure duration and required ~30 min longer to reach maximum T(c) (42.4°C). Plasma IL-6 increased at ~3 h of recovery in both genotypes, but KO mice showed a more robust sIL-6R response. Higher sIL-6R in the KO mice was associated with delayed liver p-STAT3 protein expression and attenuated serum amyloid A3 (SAA3) gene expression, suggesting the acute phase response (APR) was attenuated in these mice. Our data suggest that the absence of TNF signaling induced a regulated hypothermic state in the KO mice, TNF-IL-1 interactions may modulate T(c) and M(r) during homeostatic conditions, and TNF modulates the APR during HS recovery through interactions with the liver IL-6-STAT3 pathway of SAA3 regulation.
authors.affiliation: Thermal Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts;
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Leon
authors.forename: Shauna
authors.initials: S
authors.lastname: Dineen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blaha
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Fernandez
authors.forename: David C
authors.initials: DC
authors.lastname: Clarke
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D001481:Basal Metabolism / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D001833:Body Temperature Regulation / Q000502:physiology*; D004195:Disease Models, Animal; D018883:Heat Stroke / Q000378:metabolism* / Q000503:physiopathology*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D050796:STAT3 Transcription Factor; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: IL-6; TNF; acute phase response; heat stress; hyperthermia