JOURNAL ARTICLE

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

Sibylle von Vietinghoff, Mira Choi, Susanne Rolle, Friedrich C Luft, Ralph Kettritz
Arthritis and Rheumatism 2007, 56 (9): 3149-58
17763432

OBJECTIVE: Neutrophil activation by antineutrophil cytoplasmic autoantibodies (ANCAs) is central to the pathogenesis of the ANCA-associated vasculitides. Febrile infections occur frequently during these diseases, often in the context of immunosuppressive treatment. Heat exposure may affect the underlying pathophysiologic processes of the vasculitis. In this study we tested the hypothesis that short-term exposure to heat inhibits ANCA-induced neutrophil activation.

METHODS: After exposure to temperatures from 37 degrees C to 42 degrees C, human neutrophils were primed with either tumor necrosis factor alpha (TNFalpha) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and stimulated with monoclonal antibodies to myeloperoxidase or to proteinase 3. Respiratory burst activity was assayed using rhodamine and a nitroblue tetrazolium reduction assay. Specific inhibition experiments against p38 MAPK, ERK, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, and Western blotting with phospho-specific antibodies were used to identify key components in the antibody-induced respiratory burst.

RESULTS: A temperature-dependent reduction in ANCA-induced respiratory burst was observed over a range of heat exposures from 37 degrees C to 42 degrees C. Inhibition of human ANCA-induced neutrophil stimulation was significant at 40 degrees C (after priming with 2 ng/ml TNFalpha, mean [+/- SEM] fluorescence intensity [MFI] 114 +/- 12 at 37 degrees C versus 53 +/- 6 at 40 degrees C; after priming with 20 ng/ml GM-CSF, MFI 92 +/- 16 at 37 degrees C versus 35 +/- 6 at 40 degrees C; both P < 0.01). In the priming phase, the transient activation of the p38 MAPK, ERK, and PI 3-kinase/Akt pathways by TNFalpha was blocked by prior exposure of the neutrophils to heat, but GM-CSF-induced activation was unaltered by heat. However, in the second, antibody-induced wave of kinase activation, exposure to heat inhibited only the PI 3-kinase/Akt pathway, and these effects were independent of the priming agent used.

CONCLUSION: Short-term spikes of modest heat abrogate ANCA-induced activation of neutrophils via inhibition of PI 3-kinase/Akt signaling. Febrile responses in ANCA-mediated diseases may therefore have a physiologic purpose.

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