title: The effect of fever-like temperatures on neutrophil signaling.
abstract: The effect of fever on neutrophils has not been explored. We tested the hypothesis that fever-like temperature spikes affect neutrophil signaling and function. Prior 60 min, 42 degrees C heat exposure inhibited p38 MAPK, ERK, PI3-Kinase/Akt, and NF-kappaB activation in TNF-alpha-challenged suspended neutrophils. Using pharmacological inhibitors and an inhibitory peptide transduced into neutrophils by a HIV-TAT sequence, we found that p38 MAPK and NF-kappaB mediate TNF-alpha-mediated delayed apoptosis in suspended neutrophils. Heat exposure (39-42 degrees C) did not affect constitutive apoptosis but abrogated TNF-alpha-delayed apoptosis in these suspended cells. In contrast, adhesion-dependent functions were not inhibited. Furthermore, we found that heat exposure neither blocked p38 MAPK, ERK, and NF-kappaB activation in neutrophils on fibronectin nor prevented delayed apoptosis by TNF-alpha when cells interacted with fibronectin. Above and beyond apoptosis, TNF-alpha initiated NF-kappaB-dependent gene transcription. Heat exposure blocked this effect in suspended neutrophils but not in neutrophils on fibronectin. Finally, we show that beta2-integrins, which are not necessary for TNF-alpha-induced NF-kappaB activation at 37 degrees C, transduce costimulatory signals allowing NF-kappaB activation after heat exposure. The effect could protect circulating neutrophils from TNF-alpha activation, while not interfering with activation of adherent neutrophils. Fever could make neutrophils more parsimonious.
authors.affiliation: Medical Faculty of the Charité, Department of Nephrology and Hypertension, Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, HELIOS-Klinikum-Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Salanova
authors.forename: Mira
authors.initials: M
authors.lastname: Choi
authors.forename: Susanne
authors.initials: S
authors.lastname: Rolle
authors.forename: Maren
authors.initials: M
authors.lastname: Wellner
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Ralph
authors.initials: R
authors.lastname: Kettritz
mesh_terms: D017209:Apoptosis / Q000502:physiology; D018821:CD18 Antigens / Q000494:pharmacology; D002448:Cell Adhesion; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005334:Fever; D005353:Fibronectins / Q000502:physiology; D006358:Hot Temperature; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000502:physiology* / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005353:Fibronectins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases