J. Exp. Med., Volume 189, Number 12, June 21, 1999 1923-1930

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

By 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-1 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-1 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-1, 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.

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