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Lipoxin (LX)A₄ and Aspirin-triggered 15-epi-LXA₄ Inhibit Tumor Necrosis Factor 1–initiated Neutrophil Responses and Trafficking: Regulators of a Cytokine–Chemokine Axis

Mohamed Hachicha^*, Marc Pouliot^*, Nicos A. Petasis, and Charles N. Serhan^*

From the ^* 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; and the Department of Chemistry, University of Southern California, Los Angeles, California 90089

The impact of lipoxin A₄ (LXA₄) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-–initiated neutrophil (polymorphonuclear leukocyte) responses in vitro and in vivo using metabolically stable LX analogues. At concentrations as low as 1–10 nM, the LXA₄ and ATL analogues each inhibited TNF-–stimulated superoxide anion generation and IL-1β release by human polymorphonuclear leukocytes. These LXA₄-ATL actions were time and concentration dependent and proved selective for TNF-, as these responses were not altered with either GM-CSF– or zymosan-stimulated cells. TNF-–induced IL-1β gene expression was also regulated by both anti-LXA₄ receptor antibodies and LXA₄-ATL analogues. In murine air pouches, 15R/S-methyl-LXA₄ dramatically inhibited TNF-–stimulated leukocyte trafficking, as well as the appearance of both macrophage inflammatory peptide 2 and IL-1β, while concomitantly stimulating IL-4 in pouch exudates. Together, these results indicate that both LXA₄ and ATL regulate TNF-–directed neutrophil actions in vitro and in vivo and stimulate IL-4 in exudates, playing a pivotal role in immune responses.

Key Words: eicosanoids • leukocytes • lipid mediators • antiinflammatory receptors • wound healing

M. Hachicha's present address is Pharmacopeia, Inc., 3000 Eastpark Blvd., Cranbury, NJ 08512.

M. Hachicha and M. Pouliot contributed equally to this study.

Abbreviations used: ATLs, aspirin-triggered lipoxins; ATL analogue, 15R/S-methyl-LXA₄-methyl ester; LT, leukotriene; LX, lipoxin; LXA₄, 5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid; LXA₄ analogue, 16-phenoxy-lipoxin A₄ methyl ester; 15-epi-LXA₄, 5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid; MIP, macrophage inflammatory peptide; RA, rheumatoid arthritis; ROS, reactive oxygen species.

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