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* Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montréal, Montréal, Quebec, Canada;
Department of Chemistry, University of Southern California, Los Angeles, CA 90089; and
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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 µg/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 Ser112 and Ser136, 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 A4 (15-epi-LXA4) and its stable analog 15-epi-16-p-fluorophenoxy-LXA4, which binds to the same receptor as SAA, effectively overrode the antiapoptosis signal from SAA even when neutrophils were treated with 15-epi-LXA4 at either 1 or 4 h postculture with SAA. 15-Epi-LXA4 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-LXA4. The opposing actions of SAA and aspirin-triggered 15-epi-LXA4 may contribute to the local regulation of exacerbation and resolution of inflammation, respectively.
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1 This work was supported by Grant MOP-64283 (to J.G.F.) and Doctoral Research Awards (to L.J. and T.K.) from the Canadian Institutes of Health Research, and by Grant P50-DE016191 from the National Institutes of Health (to N.A.P. and C.N.S.).
2 D.E.K. and L.J. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. János G. Filep, Research Center, Maisonneuve-Rosemont Hospital, 5415 Boulevard de l’Assomption, Montréal, Québec, Canada H1T 2M4. E-mail address: janos.g.filep{at}umontreal.ca
4 Abbreviations used in this paper: SAA, serum amyloid A; PMN, polymorphonuclear leukocyte; LXA4, lipoxin A4; ATLa, aspirin-triggered 15-epi-16-p-fluorophenoxy-LXA4; ALX, lipoxin receptor; CMXRos, chloromethyl-X-rosamine.
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