Lipoxin A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor-α-initiated neutrophil responses and trafficking: novel regulators of a cytokine—chemokine axis relevant to periodontal diseases

Authors

  • Marc Pouliot,

    1. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • Charles N. Serhan

    Corresponding author
    1. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Charles N. Serhan, Center for Experimental Therapeutics and Reperfusron Injury, Thorn Building for Medical Research, 7th Floor, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA Tel: 617 732 8822 Fax: 617 278 6957 e-mail: cnserhan@zeus.bwh.harvard.edu

Abstract

The impact of lipoxin A4 (LXA4) and aspirin-triggered-lipoxins (ATL) was investigated in tumor necrosis factor (TNFα)-initiated neutrophil (PMN) responses in vitro and in vivo using LX analogs that are metabolically more stable. At nanoraolar levels, the LXA4 and ATL analog 15 R/S-methyl-LXA4 each blocked TNFa-stimulated IL-1β release by isolated human PMN in vitro. These LXA4-ATL actions were time- and concentration-dependent. The TNFα-induced IL-1β gene expression was also regulated by 15 R/S-methyl-LXA4. In addition, 15 R/S-methyl-LXA4 added to murine air pouches dramatically inhibited TNFα-stimulated leukocyte trafficking in vivo, as well as altered the appearance of both macrophage inflammatory peptide-2 and IL-1 ji and concomitantly stimulated IL-4 in pouch exudates. These findings from in vitro and in vivo experiments indicate that both LXA4 and ATL are regulators of TNFα-directed neutrophil actions and stimulate IL-4 in exudates and thus regulate mediators that are held to play an important role in the pathogenesis of periodontal disease.

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