title: The survival effect of TNF-alpha in human neutrophils is mediated via NF-kappa B-dependent IL-8 release.
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-alpha in human neutrophils involves activation of both NF-kappa B and phosphoinositide 3-kinase (PI3-kinase) pathways. In this study, we address how these pathways integrate to prevent cell death. In human neutrophils, TNF-alpha (200 U/ml) induced rapid I kappa B-alpha degradation, NF-kappa B 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 I kappa B-alpha degradation or NF-kappa B activation compared to control. Importantly, inhibition of PI3-kinase did not modify TNF-alpha -induced I kappa B-alpha degradation, yet fully inhibited the survival effect of both cytokines. Inhibition of I kappa B-alpha 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 effect of TNF-alpha and inhibited its late survival effect without affecting GM-CSF-induced survival. These data suggest that cross-talk between NF-kappa B and PI3-kinase pathways in TNF-alpha -stimulated neutrophils results from NF-kappa B/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-kappa B activation or IL-8 release.
authors.affiliation: Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, GB. asc32@hermes.cam.ac.uk
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.forename: John
authors.initials: J
authors.lastname: Deighton
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002450:Cell Communication / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002867:Chromones; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020672:I-kappa B Proteins; D016209:Interleukin-8; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C416282:BAY 11-7085; C002669:parthenolide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one