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.

Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

“…Further investigations are needed to address these differential effects of heat. We reported earlier that NF-B controls neutrophil survival, and that moderate heat in vitro abrogates the NF-B-dependent signals in neutrophils after challenge with TNF␣ and lipopolysaccharide (LPS) (17,18,29). We observed the same NF-B inhibition in neutrophils isolated from mice that were exposed to 40.5°C for 30 minutes (18), suggesting that these effects also occur under in vivo conditions.…”

“…The signaling and functions of neutrophils are modulated by short-term exposures to heat. We demonstrated previously that moderate, short-term increases in temperature can block activation of NF-B in neutrophils, and thereby abrogate antiapoptotic signals (17,18). The inhibitory effect of heat on neutrophil signaling was also detected in mice that were exposed to a short-term fever spike of 40.5°C (18), indicating that the effects of heat are relevant in vivo.…”

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

“…Similarly, we observed no heat effect in a previous study using TNF-␣ to stimulate neutrophil adhesion to fibronectin. 29 Our inhibitor studies revealed that migration in response to both chemokines was mediated by PI3-K/Akt and ERK, but not by JNK or p38 MAPK, and that short-term heat exposure inhibited PI3-K/Akt with a marginal effect on ERK activation. These experiments support the notion that heat-mediated inhibition of migration was, at least in part, a consequence of PI3-K/Akt abrogation.…”

“…Interestingly, we found recently that heat was not able to block NF-B activation of TNF-␣-stimulated neutrophils on fibronectin, underscoring the importance of preventing TNF-␣ generation upstream. 29 When we used more complex settings by exposing mice to 37°C or 40°C for 60 minutes followed by ex vivo stimulation of isolated bone marrow neutrophils with GM-CSF on fibronectin, we observed strong NF-B activation with 37°C and significant inhibition with exposure to 40°C. Thus, heat exposure in cell culture experiments and exposure of the whole animal produced similar results with respect to NF-B inhibition.…”

“…Quantitative RT-PCR was performed as described previously using TaqMan technology (Applied Biosystems, Weiterstadt, Germany). 29 Reverse transcription was performed according to the Superscript protocol (Invitrogen, De Schelp, The Netherlands). TaqMan RT-PCR was performed using the Master Mix (Applied Biosystems).…”