title: Inhibition of neutrophil apoptosis by type 1 IFN depends on cross-talk between phosphoinositol 3-kinase, protein kinase C-delta, and NF-kappa B signaling pathways.
abstract: Neutrophils are abundant, short-lived leukocytes with a key role in the defense against rapidly dividing bacteria. They enter apoptosis spontaneously within 24-48 h of leaving the bone marrow. However, their life span can be extended during inflammatory responses by several proinflammatory cytokines. Inappropriate survival of neutrophils contributes to chronic inflammation and tissue damage associated with diseases such as rheumatoid arthritis. We have previously reported that type I IFNs can inhibit both cytokine deprivation and Fas-induced apoptosis in activated T cells. IFN-beta locally produced by hyperplastic fibroblasts within the pannus tissue of patients with rheumatoid arthritis contributes to the inappropriately extended life span of infiltrating T cells. Type I IFNs are equally effective at delaying spontaneous apoptosis in human neutrophils. In the work presented here we investigated the signaling pathways involved in mediating this effect. The antiapoptotic actions of IFN-beta were targeted at an early stage of neutrophil apoptosis, occurring upstream of mitochondrial permeability transition, and were phosphatidylinositol 3-kinase (PI3K) dependent, as they were blocked by the PI3K inhibitor LY294002. Analysis of signaling pathways downstream of PI3K revealed that the antiapoptotic effect of type 1 IFN was inhibited by rottlerin, SN50, and cycloheximide, indicating requirements for activation of protein kinase C-delta, NF-kappaB, and de novo protein synthesis, respectively. Moreover, EMSA was used to show that the activation of NF-kappaB occurred downstream of PI3K and protein kinase C-delta activation. We conclude that type I IFNs inhibit neutrophil apoptosis in a PI3K-dependent manner, which requires activation of protein kinase C-delta and induction of NF-kappaB-regulated genes.
authors.affiliation: Medical Research Council Center for Immune Regulation, Birmingham University, Birmingham, United Kingdom.
authors.forename: KeQing
authors.initials: K
authors.lastname: Wang
authors.forename: Dagmar
authors.initials: D
authors.lastname: Scheel-Toellner
authors.forename: See Heng
authors.initials: SH
authors.lastname: Wong
authors.forename: Rachel
authors.initials: R
authors.lastname: Craddock
authors.forename: Jorge
authors.initials: J
authors.lastname: Caamano
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.forename: Mike
authors.initials: M
authors.lastname: Salmon
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology*; D007425:Intracellular Membranes / Q000276:immunology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008928:Mitochondria / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051745:Protein Kinase C-delta; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D003513:Cycloheximide; D016898:Interferon-alpha; D016899:Interferon-beta; D007527:Isoenzymes; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C497258:PRKCD protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human