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Am J Physiol Cell Physiol 287: C422-C431, 2004. First published April 7, 2004; doi:10.1152/ajpcell.00507.2003
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RECEPTORS AND SIGNAL TRANSDUCTION

Hypothermia prolongs activation of NF-{kappa}B and augments generation of inflammatory cytokines

Karen D. Fairchild,1 Ishwar S. Singh,2 Sandip Patel,1 Beth E. Drysdale,4 Rose M. Viscardi,1 Lisa Hester,2,3 Heather M. Lazusky,1 and Jeffrey D. Hasday2,3,4

Departments of 1Pediatrics and 2Medicine, University of Maryland School of Medicine; 3University of Maryland at Baltimore Cytokine Core Laboratory; and 4Medicine and Research Services of the Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201

Submitted 17 November 2003 ; accepted in final form 1 April 2004

While moderate hypothermia is protective against ischemic cardiac and brain injury, it is associated with much higher mortality in patients with sepsis. We previously showed that in vitro exposure to moderate hypothermia (32°C) delays the induction and prolongs the duration of TNF-{alpha} and IL-1{beta} secretion by lipopolysaccharide (LPS)-stimulated human mononuclear phagocytes. In the present study, we extended these observations by showing that moderate hypothermia exerts effects on TNF-{alpha} and IL-1{beta} generation in the human THP-1 monocyte cell line that are similar to those that we previously found in primary cultured monocytes; that hypothermia causes comparable changes in cytokine generation stimulated by zymosan, toxic shock syndrome toxin-1, and LPS; and that hypothermia causes similar changes in TNF-{alpha} and IL-1{beta} mRNA accumulation. TNF-{alpha} mRNA half-life, determined after transcriptional arrest with actinomycin D, was not significantly prolonged by lowering incubation temperature from 37 to 32°C, suggesting that hypothermia modifies TNF-{alpha} gene transcription. This finding was further supported by reporter gene studies showing a threefold increase in activity of the human TNF-{alpha} promoter at 32 vs. 37°C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NF-{kappa}B activation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNF-{alpha} and IL-1{beta} production. Delayed reexpression of the inhibitor I{kappa}B{alpha}, shown by Northern blotting and immunoblotting, may account in part for the prolonged NF-{kappa}B activation at 32°C. Augmentation of NF-{kappa}B-dependent gene expression during prolonged exposure to hypothermia may be a common mechanism leading to increased lethality in sepsis, late-onset systemic inflammatory response syndrome after accidental hypothermia, and neuroprotection after ischemia.

tumor necrosis factor; I{kappa}B; monocyte; lipopolysaccharide; interleukin-1


Address for reprint requests and other correspondence: K. D. Fairchild, Div. of Neonatology, Rm. N5W68, Univ. of Maryland Hospital, 22 S. Greene St., Baltimore, MD 21201 (E-mail: kfairchild{at}peds.umaryland.edu).




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