The impact of lipoxin A4 (LXA4) and aspirin-triggered-lipoxins (ATL) was investigated in tumor necrosis factor (TNF alpha)-initiated neutrophil (PMN) responses in vitro and in vivo using LX analogs that are metabolically more stable. At nanomolar levels, the LXA4 and ATL analog 15 R/S-methyl-LXA4 each blocked TNF alpha-stimulated IL-1 beta release by isolated human PMN in vitro. These LXA4-ATL actions were time- and concentration-dependent. The TNF alpha-induced IL-1 beta 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 TNF alpha-stimulated leukocyte trafficking in vivo, as well as altered the appearance of both macrophage inflammatory peptide-2 and IL-1 beta 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 TNF alpha-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.