Short-term heat exposure inhibits inflammation by abrogating recruitment of and nuclear factor-{kappa}B activation in neutrophils exposed to chemotactic cytokines.
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 beta2-integrin co-stimulation, allowing GM-CSF and IL-8 to activate nuclear factor (NF)-kappaB, 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-kappaB activation in a mouse model of skin inflammation. Mice that were exposed to 40 degrees 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-kappaB 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-kappaB activation was seen in the inflammatory lesions of mice exposed to fever-like temperatures as demonstrated by in situ hybridization for IkappaBalpha mRNA. These new findings suggest that heat may have anti-inflammatory effects in neutrophil-dependent inflammation.
Choi
Mira
M
HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany.
Salanova
Birgit
B
Rolle
Susanne
S
Wellner
Maren
M
Schneider
Wolfgang
W
Luft
Friedrich C
FC
Kettritz
Ralph
R
D000818:Animals; D017305:Annexin A1 / Q000096:biosynthesis; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002448:Cell Adhesion; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D017403:In Situ Hybridization; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D039661:Integrin beta3 / Q000096:biosynthesis; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D053700:Receptors, Interleukin-8 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013995:Time
D017305:Annexin A1; D016207:Cytokines; D039661:Integrin beta3; D016328:NF-kappa B; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D053700:Receptors, Interleukin-8