Attenuated thermoregulatory, metabolic, and liver acute phase protein response to heat stroke in TNF receptor knockout mice
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 B6129F(2) (wild type, WT) and TNFR KO mice. Before heat exposure, TNFR KO mice showed similar to 0.4 degrees C lower core temperature (T-c; radiotelemetry), similar to 10% lower metabolic rate (M-r; indirect calorimetry), and reduced plasma interleukin (IL)-1 alpha 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 Mr than WT mice for a given heat exposure duration and required similar to 30 min longer to reach maximum T-c (42.4 degrees C). Plasma IL-6 increased at similar to 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 Mr during homeostatic conditions, and TNF modulates the APR during HS recovery through interactions with the liver IL-6-STAT3 pathway of SAA3 regulation.
|Título según WOS:||ID WOS:000328749700002 Not found in local WOS DB|
|Título de la Revista:||AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY|
|Editorial:||AMER PHYSIOLOGICAL SOC|
|Fecha de publicación:||2013|
|Página de inicio:||R1421|