The stress response decreases NF-kappaB activation in liver of endotoxemic mice.
Recent studies suggest that the stress (heat shock) response protects cells and tissues from inflammatory and other noxious insults. The transcription factor nuclear factor-kappa B (NF-kappaB), normally sequestered in the cytoplasm by its inhibitory protein IkappaB, regulates many genes involved in the inflammatory response to critical illness. Endotoxemia is associated with increased NF-kappaB activity in liver but the effect of the stress response on endotoxin-induced NF-kappaB activation in the liver is not known. We hypothesized that the stress response inhibits NF-kappaB DNA binding activity in liver during endotoxemia. The stress response was induced in mice by hyperthermia (42 degrees C for 3 min) or sodium arsenite (10 mg/kg) and resulted in increased hepatic heat shock protein-72 levels. After induction of the stress response, mice were injected subcutaneously with endotoxin (12.5 mg/kg) or a corresponding volume of sterile saline. NF-kappaB DNA binding activity in the nuclear fraction of liver tissue increased and cytoplasmic IkappaB-alpha levels decreased after endotoxin injection, with a maximal effect seen at 60 min. The endotoxin-induced increase in NF-kappaB DNA binding activity and decrease in IkappaB-alpha levels were inhibited by prior induction of the stress response. In additional experiments, treatment of mice with sodium arsenite after induction of endotoxemia blunted the increase in NF-kappaB activity, indicating a therapeutic potential of sodium arsenite, in addition to its preventive effect. The present results suggest that the protective effects of the stress response in vivo may, at least in part, be due to inhibited NF-kappaB activation.
Pritts
Timothy A
TA
Department of Surgery, University of Cincinnati, Ohio 45267-0558, USA.
Wang
Quan
Q
Sun
Xiaoyan
X
Fischer
David R
DR
Hungness
Eric S
ES
Fischer
Josef E
JE
Wong
Hector R
HR
Hasselgren
Per-Olof
PO
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D018869:Heat-Shock Response / Q000502:physiology*; D006979:Hyperthermia, Induced; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D017670:Sodium Compounds / Q000494:pharmacology
D018053:Arsenites; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017670:Sodium Compounds; C017947:sodium arsenite; D004247:DNA