Lipoxin A<sub>4</sub>and aspirin-triggered 15-epi-lipoxin A<sub>4</sub>inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes
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- Levente József
- Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4; 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
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- Christine Zouki
- Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4; 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
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- Nicos A. Petasis
- Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4; 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
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- Charles N. Serhan
- Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4; 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
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- János G. Filep
- Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4; 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
書誌事項
- 公開日
- 2002-09-16
- DOI
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- 10.1073/pnas.202296999
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>Lipoxin A<jats:sub>4</jats:sub>(LXA<jats:sub>4</jats:sub>) and aspirin-triggered 15-epi-LXA<jats:sub>4</jats:sub>(ATL) are emerging as endogenous braking signals for neutrophil-mediated tissue injury. Recent studies indicate that peroxynitrite (ONOO<jats:sup>−</jats:sup>) may function as an intracellular signal for the production of IL-8, a potent proinflammatory cytokine in human leukocytes. In this study, we evaluated the impact of the metabolically stable analogues of LXA<jats:sub>4</jats:sub>/ATL on lipopolysaccharide (LPS)-induced ONOO<jats:sup>−</jats:sup>formation and ONOO<jats:sup>−</jats:sup>-mediated IL-8 gene expression in human leukocytes. At nanomolar concentrations, LXA<jats:sub>4</jats:sub>analogues markedly reduced LPS-stimulated superoxide formation, evoked increases in intracellular diamino-fluorescein fluorescence (an indicator of NO formation), and consequently reduced ONOO<jats:sup>−</jats:sup>formation in isolated neutrophils, as well as in neutrophils, monocytes, and lymphocytes, in whole blood. LXA<jats:sub>4</jats:sub>/ATL analogues attenuated nuclear accumulation of activator protein-1 and nuclear factor-κB in both polymorphonuclear and mononuclear leukocytes and inhibited IL-8 mRNA expression and IL-8 release by 50–65% in response to LPS. The LXA<jats:sub>4</jats:sub>inhibitory responses were concentration dependent and were not shared by 15-deoxy-LXA<jats:sub>4</jats:sub>. None of the LXA<jats:sub>4</jats:sub>analogues studied affected neutrophil survival, nor reversed the apoptosis delaying action of LPS in neutrophils. In addition, LXA<jats:sub>4</jats:sub>analogues had no significant effect on exogenous ONOO<jats:sup>−</jats:sup>-induced IL-8 gene and protein expression. These findings suggest that by attenuating ONOO<jats:sup>−</jats:sup>formation, LXA<jats:sub>4</jats:sub>and ATL can oppose ONOO<jats:sup>−</jats:sup>signaling in leukocytes and provide a rationale for using stable synthetic analogues as antiinflammatory compounds<jats:italic>in vivo</jats:italic>.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 99 (20), 13266-13271, 2002-09-16
Proceedings of the National Academy of Sciences
