Lipoxin (LX)A(4) and aspirin-triggered 15-epi-LXA(4) inhibit tumor necrosis factor 1 alpha-initiated neutrophil responses and trafficking: Regulatorsof a cytokine-chemokine axis

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