title: Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation.
abstract: Elevated plasma levels of the acute-phase reactant serum amyloid A (SAA) have been used as a marker and predictor of inflammatory diseases. SAA regulates leukocyte activation; however, it is not known whether it also modulates neutrophil apoptosis, which is critical to the optimal expression and resolution of inflammation. Culture of human neutrophils with SAA (0.1-20 microg/ml) markedly prolonged neutrophil longevity by delaying constitutive apoptosis. SAA evoked concurrent activation of the ERK and PI3K/Akt signaling pathways, leading to phosphorylation of BAD at Ser(112) and Ser(136), respectively, and to prevention of collapse of mitochondrial transmembrane potential, cytochrome c release, and caspase-3 activation. These actions were abrogated by pharmacological inhibition of the formyl peptide receptor, ERK or PI3K. Furthermore, aspirin-triggered 15-epi-lipoxin A(4) (15-epi-LXA(4)) and its stable analog 15-epi-16-p-fluorophenoxy-LXA(4), which binds to the same receptor as SAA, effectively overrode the antiapoptosis signal from SAA even when neutrophils were treated with 15-epi-LXA(4) at either 1 or 4 h postculture with SAA. 15-Epi-LXA(4) itself did not affect neutrophil survival and apoptosis. Our results indicate that SAA at clinically relevant concentrations promotes neutrophil survival by suppressing the apoptotic machinery, an effect that can be opposed by 15-epi-LXA(4). The opposing actions of SAA and aspirin-triggered 15-epi-LXA(4) may contribute to the local regulation of exacerbation and resolution of inflammation, respectively.
authors.affiliation: Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montréal, 5415 Boulevard de l'Assomption, Montréal, Quebec, Canada.
authors.forename: Driss
authors.initials: D
authors.lastname: El Kebir
authors.forename: Levente
authors.initials: L
authors.lastname: József
authors.forename: Tarek
authors.initials: T
authors.lastname: Khreiss
authors.forename: Wanling
authors.initials: W
authors.lastname: Pan
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: János G
authors.initials: JG
authors.lastname: Filep
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D044045:Lipoxins / Q000378:metabolism / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D044067:Receptors, Lipoxin / Q000502:physiology; D000685:Serum Amyloid A Protein / Q000502:physiology*; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D044045:Lipoxins; D044067:Receptors, Lipoxin; D000685:Serum Amyloid A Protein; C040527:lipoxin A4; D001241:Aspirin