Hypothermia prolongs activation of NF- and augments generation of inflammatory cytokines

Fairchild, Karen D., Ishwar S. Singh, Sandip Patel, Beth E. Drysdale, Rose M. Viscardi, Lisa Hester, Heather M. Lazusky, and Jeffrey D. Hasday. Hypothermia prolongs activation of NFand augments generation of inflammatory cytokines. Am J Physiol Cell Physiol 287: C422–C431, 2004. First published April 7, 2004; 10.1152/ajpcell.00507.2003.—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 TNFand 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 TNFand IL-1 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 TNFand IL-1 mRNA accumulation. TNFmRNA 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 TNFgene transcription. This finding was further supported by reporter gene studies showing a threefold increase in activity of the human TNFpromoter at 32 vs. 37°C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NFactivation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNFand IL-1 production. Delayed reexpression of the inhibitor I B , shown by Northern blotting and immunoblotting, may account in part for the prolonged NFactivation at 32°C. Augmentation of NF-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.