Lipoxins display selective activities on human leukocytes that are either stimulatory or inhibitory, depending on the target cell type involved. In human PMN, LXA 4 induces chemokinesis but inhibits chemotaxis toward leukotriene B 4 (LTB 4 ) and N-formylmethionylleucylphenylalanine (FMLP) (7). LXA 4 also inhibits FMLP-induced PMN transmigration across intestinal epithelium (8). In addition, LTB 4 -and LTC 4 -induced PMN adherence to human umbilical vein endothelial cells (HUVEC) is reduced by ϳ70% by LXA 4 and LXB 4 (9) and aspirin-triggered 15-epi-LXA 4 also inhibits LTB 4 -stimulated PMN adherence to HUVEC at nanomolar concentrations and is ϳtwo times more potent than LXA 4 in this setting (6). LXA 4 and LXB 4 also down-regulate peptidoleukotriene-induced Pselectin expression on HUVEC (9). LXA 4 displays in vivo activity, with inhibition of PMN migration into the kidney in rat glomerulonephritis models (3) and inhibition of PMN diapedesis from postcapillary venules (10). In contrast to the downregulation of PMN, LX exhibit selective stimulatory activities in the monocyte, as we recently described potent activation of human monocyte migration and adherence to laminin by both LXA 4 and LXB 4 (11).Human monocytes were also found to rapidly convert more than 80% of added LXA 4 to novel metabolites via dehydrogenation and reduction of double bonds and the products were identified as 15-oxo-LXA 4

The impact of  lipoxin A4 (LXA4) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-α–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-α–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-α, as these responses were not altered with either GM-CSF– or zymosan-stimulated cells. TNF-α–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-α–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-α–directed neutrophil actions in vitro and in vivo and stimulate IL-4 in exudates, playing a pivotal role in immune responses.