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Fever-Like Temperatures Affect Neutrophil NF-B Signaling, Apoptosis, and ANCA-Antigen Expression

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

Address correspondence to: Dr. Ralph Kettritz, Wiltbergstrasse 50, 13125 Berlin, Germany. Phone: +49-30-9417-2202; Fax: +49-30-9417-2206; E-mail: kettritz{at}charite.de

Received for publication September 13, 2005. Accepted for publication February 15, 2005.

The neutrophil is pivotal to ANCA vasculitis pathogenesis. Fever frequently complicates ANCA diseases. This study investigated the effects of short-term heat exposure on apoptosis in neutrophils that were treated with LPS, GM-CSF, IL-8, and dexamethasone. All compounds delayed apoptosis. Heat abrogated the apoptosis-delaying effect of LPS without affecting constitutive apoptosis or delayed apoptosis by GM-CSF, IL-8, or dexamethasone. The heat effect was dose dependent over the 39 to 42°C range. NF-B but not extracellular signal–regulated kinase, p38 mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3-kinase/Akt controlled LPS-delayed apoptosis. Furthermore, LPS-induced IB degradation, DNA binding, and NF-B–dependent gene transcription activation were abrogated by short-term heat. When core temperatures were raised to 40.5°C for 30 min in mice, LPS-induced neutrophil NF-B activation also was prevented. Short-term heat removed heat-shock protein 90 from the IB kinase complex, resulting in failure of LPS-induced IB kinase activation. Despite delayed apoptosis, ANCA antigen expression was increased in LPS-treated neutrophils. ANCA antigen increase was prevented by p38 MAPK inhibition and by heat exposure. Heat exposure did not inhibit LPS-induced p38 MAPK phosphorylation. Instead, apoptosis-mediated p38 MAPK degradation was accelerated, thereby decreasing the p38 MAPK that was available for LPS-mediated ANCA antigen upregulation. These data suggest that fever-like temperatures modulate neutrophil behavior in this disease.

This article has been cited by other articles:

				M. Choi, B. Salanova, S. Rolle, M. Wellner, W. Schneider, F. C. Luft, and R. Kettritz Short-Term Heat Exposure Inhibits Inflammation by Abrogating Recruitment of and Nuclear Factor-{kappa}B Activation in Neutrophils Exposed to Chemotactic Cytokines Am. J. Pathol., February 1, 2008; 172(2): 367 - 777. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673