Published online before print January 10, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070532

Accepted for publication October 18, 2007.

Article

Short-Term Heat Exposure Inhibits Inflammation by Abrogating Recruitment of and Nuclear Factor-B Activation in Neutrophils Exposed to Chemotactic Cytokines

Mira Choi^*, Birgit Salanova^*, Susanne Rolle^*, Maren Wellner, Wolfgang Schneider, Friedrich C. Luft^*, and Ralph Kettritz^*@

From the Department of Nephrology and Hypertension,* Medical Faculty of the Charité, and the Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Helios-Klinikum, Berlin, Germany

^@ To whom correspondence should be addressed. E-mail: kettritz{at}charite.de.

	Abstract

Cytokines, such as granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-8 attract neutrophils into inflammatory sites. During emigration from the blood neutrophils interact with extracellular matrix proteins such as fibronectin. Fibronectin provides 2-integrin co-stimulation, allowing GM-CSF and IL-8 to activate nuclear factor (NF)-B, an effect that does not occur in suspension. We tested the hypothesis that exposure of mice to fever-like temperatures abrogates neutrophil recruitment and NF-B activation in a mouse model of skin inflammation. Mice that were exposed to 40°C for 1 hour showed strongly reduced GM-CSF- and IL-8-induced neutrophilic skin inflammation. In vitro heat exposure did not interfere with neutrophil adhesion or spreading on fibronectin but strongly inhibited migration toward both cytokines. Using specific inhibitors, we found that PI3-K/Akt was pivotal for neutrophil migration and that heat down-regulated this pathway. Furthermore, neutrophils on fibronectin showed abrogated NF-B activation in response to GM-CSF and IL-8 after heat. In vivo heat exposure of mice followed by ex vivo stimulation of isolated bone marrow neutrophils confirmed these results. Finally, less NF-B activation was seen in the inflammatory lesions of mice exposed to fever-like temperatures as demonstrated by in situ hybridization for IB mRNA. These new findings suggest that heat may have anti-inflammatory effects in neutrophil-dependent inflammation.