Fever-like temperatures affect neutrophil NF-kappaB signaling, apoptosis, and ANCA-antigen expression.
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 degrees C range. NF-kappaB but not extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3-kinase/Akt controlled LPS-delayed apoptosis. Furthermore, LPS-induced IkappaBalpha degradation, DNA binding, and NF-kappaB-dependent gene transcription activation were abrogated by short-term heat. When core temperatures were raised to 40.5 degrees C for 30 min in mice, LPS-induced neutrophil NF-kappaB activation also was prevented. Short-term heat removed heat-shock protein 90 from the IkappaB kinase complex, resulting in failure of LPS-induced IkappaB 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.
Kettritz
Ralph
R
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. kettritz@charite.de
Choi
Mira
M
Salanova
Birgit
B
Wellner
Maren
M
Rolle
Susanne
S
Luft
Friedrich C
FC
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D000941:Antigens / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001831:Body Temperature / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D005334:Fever / Q000276:immunology* / Q000473:pathology; D006358:Hot Temperature; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology*; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D014657:Vasculitis / Q000276:immunology* / Q000473:pathology
D019268:Antibodies, Antineutrophil Cytoplasmic; D000941:Antigens; D016328:NF-kappa B