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The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 release

2004; Wiley; Volume: 34; Issue: 6 Linguagem: Inglês

10.1002/eji.200425091

1521-4141

Andrew S. Cowburn, John Deighton, Sarah R. Walmsley, Edwin R. Chilvers,

Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Abstract The capacity of cytokines to modulate neutrophil apoptosis is thought to be a major factor influencing the resolution of granulocytic inflammation. We have previously shown that the late survival effect of TNF‐α in human neutrophils involves activation of both NF‐κB and phosphoinositide 3‐kinase (PI3‐kinase) pathways. In this study, we address how these pathways integrate to prevent cell death. In human neutrophils, TNF‐α (200 U/ml) induced rapid IκB‐α degradation, NF‐κB activation and IL‐8 release (31.8±5.4 pg/10 5 cells/2 h), whereas GM‐CSF (10 ng/ml) stimulated an equivalent IL‐8 release (26.5±4.5 pg/10 5 cells/2 h) without enhanced IκB‐α degradation or NF‐κB activation compared to control. Importantly, inhibition of PI3‐kinase did not modify TNF‐α ‐induced IκB‐α degradation, yet fully inhibited the survival effect of both cytokines. Inhibition of IκB‐α phosphorylation, PI3‐kinase or ERK1/2 activation blocked IL‐8 release by both cytokines. Blocking IL‐8 activity by inhibiting its synthesis or by using a neutralizing antibody enhanced the early pro‐apoptotic effectof TNF‐α and inhibited its late survival effect without affecting GM‐CSF‐induced survival. These data suggest that cross‐talk between NF‐κB and PI3‐kinase pathways in TNF‐α ‐stimulated neutrophils results from NF‐κB/ERK1/2‐dependent IL‐8 production which acts in an autocrine manner to drive PI3‐kinase‐dependent survival. In contrast, GM‐CSF‐mediated survival does not involve NF‐κB activation or IL‐8 release.