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E Himpe, FARC, VUB, Brussels, 1090, Belgium
C Degaillier, FARC, VUB, Jette, Belgium
A Coppens, FARC, VUB, Brussels, Belgium
R Kooijman, FARC, VUB, Jette, Belgium

Correspondence: Eddy Himpe, Email: eddy.himpe{at}vub.ac.be

Abstract

Apoptosis of human neutrophils is a crucial mechanism for the resolution of inflammation. We previously showed that insulin-like growth factor-I (IGF-I) delays spontaneous neutrophil apoptosis without influencing the secretion of cytokines by these cells. In the present study, we further addressed the role of IGF-I in regulating neutrophil survival in the presence of other factors present during inflammation, and the mechanism involved in delaying apoptosis. We show that IGF-I delays neutrophil apoptosis triggered by the agonistic anti-Fas antibody CH11 and that the effect of IGF-I is comparable in magnitude with those of the acknowledged anti-apoptotic cytokines interferon- (IFN) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, IGF-I exerted additional effects on cell survival in the presence of these cytokines. IGF-I did not affect Fas expression or activation by anti-Fas of caspase-8, but inhibited the depolarization of the mitochondrial membrane. Inhibitor studies indicate that the phosphatidylinositol-3 kinase (PI3K) pathway, but not the MEK-ERK pathway mediates the effects of IGF-I. However, in contrast to GM-CSF, IGF-I did not induce phosphorylation and translocation to the membrane of Akt, the canonical downstream target of PI3K. We therefore speculate that other downstream targets of PI3K are involved in the delaying neutrophil apoptosis by IGF-I, possibly through stabilization of the mitochondrial membrane.