title: Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1.
abstract: During immune responses, neutrophils must integrate survival and death signals from multiple sources to regulate their lifespan. Signals that activate either the Bcl-2- or death receptor-regulated apoptosis pathways can provide powerful stimuli for neutrophils to undergo cell death, but whether they act cooperatively in parallel or directly cross-talk in neutrophils is not known. Previous studies suggested that Bcl-2 family proteins are not required for Fas-induced cell death in neutrophils, but did not examine whether they could modulate its rapid onset. By monitoring the rate of change in neutrophil viability associated with activation of the Fas-triggered death receptor pathway using real-time cell imaging, we show that the Bcl-2-related proteins Bid, Bax, and Bak accelerate neutrophil apoptosis but are not essential for cell death. Increased Bcl-2 or Mcl-1 expression prevents efficient induction of apoptosis by Fas stimulation indicating that the Bcl-2-regulated apoptosis pathway can directly interfere with Fas-triggered apoptosis. Fas has been shown to initiate NFκB activation and gene transcription in cell lines, however gene transcription is not altered in Fas-activated Bid(-/-) neutrophils, indicating that apoptosis occurs independently of gene transcription in neutrophils. The specification of kinetics of neutrophil apoptosis by Bid impacts on the magnitude of neutrophil IL-1β production, implicating a functional role for the Bcl-2-regulated pathway in controlling neutrophil responses to FasL. These data demonstrate that the intrinsic apoptosis pathway directly controls the kinetics of Fas-triggered apoptosis in neutrophils.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. croker@wehi.edu.au
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Grant
authors.initials: G
authors.lastname: Dewson
authors.forename: Kirsteen J
authors.initials: KJ
authors.lastname: Campbell
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Rogers
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: White
authors.forename: Kurt
authors.initials: K
authors.lastname: Lackovic
authors.forename: Louise H
authors.initials: LH
authors.lastname: Cengia
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cory
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C501332:ABT-737; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor