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B and augments generation of inflammatory cytokines
1 Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
2 Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
3 Medicine and Research Services, Baltimore VA Medical Center, Baltimore, MD, USA
4 Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Medicine and Research Services, Baltimore VA Medical Center, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: kfairchild{at}peds.umaryland.edu.
While moderate hypothermia is protective against ischemic cardiac and brain injury (7), it is associated with much higher mortality in patients with sepsis. We previously showed that in vitro exposure to moderate hypothermia (32°C) delays induction and prolongs duration of TNF
and IL-1
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 and IL-1 generation in the human THP-1 monocyte cell line similar to those we previously found in primary cultured monocytes, that hypothermia causes comparable changes in cytokine generation stimulated by zymosan, TSST-1, and LPS, and that hypothermia causes similar changes in TNF and IL-1 mRNA accumulation. TNF 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 gene transcription. This was further supported by reporter gene studies showing a 3-fold increase in activity of the human TNF promoter at 32° vs 37°C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NF-
B activation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNF and IL-1 expression. Delayed reexpression of IB, shown by Northern and immunoblotting, may account in part for the prolonged NF-B activation at 32°C. Augmentation of NF-B-dependent gene expression during prolonged exposure to hypothermia might be a common mechanism leading to increased lethality in sepsis, late onset systemic inflammatory response syndrome after accidental hypothermia, and neuroprotection following ischemia.
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  L. A. Sonna, M. M. Kuhlmeier, H. C. Carter, J. D. Hasday, C. M. Lilly, and K. D. Fairchild Effect of moderate hypothermia on gene expression by THP-1 cells: a DNA microarray study Physiol Genomics, September 14, 2006; 26(1): 91 - 98. [Abstract] [Full Text] [PDF]
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 C. K. Ganta, B. G. Helwig, F. Blecha, R. R. Ganta, R. Cober, S. Parimi, T. I. Musch, R. J. Fels, and M. J. Kenney Hypothermia-enhanced splenic cytokine gene expression is independent of the sympathetic nervous system Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R558 - R565. [Abstract] [Full Text] [PDF]
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 K. D. Fairchild, I. S. Singh, H. C. Carter, L. Hester, and J. D. Hasday Hypothermia enhances phosphorylation of I{kappa}B kinase and prolongs nuclear localization of NF-{kappa}B in lipopolysaccharide-activated macrophages Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1114 - C1121. [Abstract] [Full Text] [PDF]
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