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CELLULAR METABOLISM

Hypothermia enhances phosphorylation of IB kinase and prolongs nuclear localization of NF-B in lipopolysaccharide-activated macrophages

¹Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, Virginia; Departments of ²Pediatrics and ³Medicine, University of Maryland School of Medicine; ⁴University of Maryland at Baltimore Cytokine Core Laboratory; and ⁵Medicine and Research Services of the Baltimore Veterans Affairs Medical Center, Baltimore, Maryland

Submitted 1 April 2005 ; accepted in final form 10 June 2005

Hypothermia (HT) has been associated with both beneficial and detrimental consequences in various pathophysiological states. While HT is generally thought to have anti-inflammatory and cytoprotective effects, we have previously shown that moderate in vitro HT prolongs TNF- production by LPS-stimulated mononuclear phagocytes, in part by prolonging TNF- gene transcription and activation of the pleiotropic transcription factor NF-B. In this study, we have further characterized the effect of moderate (32°C) and marked (28°C) HT in human monocytic THP-1 cells by showing that even short (2 h) exposure to HT followed by a return to normothermic conditions for 22 h resulted in augmented and prolonged production of TNF-. Production of heat shock protein 72 and activation of heat shock factor 1 are not affected by HT in these studies, suggesting that the effect is not part of a generalized stress response. Using immunoblotting, we have shown that HT augments phosphorylation of IKK- and IKK- (up to an 8-fold increase at 28°C and a 3.6-fold increase at 32°C vs. 37°C). Furthermore, nuclear accumulation of NF-B p65 was significantly prolonged in hypothermic cells (1.4- and 2.5-fold more nuclear p65 at 2 and 4 h at 28 vs. 37°C). Reexpression of IB-, which contributes to the termination of NF-B-dependent transcription, was delayed several hours in HT-exposed cells. Thus we have shown that clinically relevant HT alters both cytosolic and nuclear events responsible for NF-B activation and deactivation. Enhanced NF-B activation may contribute to the immunomodulatory effects of HT in various clinical settings.

tumor necrosis factor; monocytes