Lipoxin A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor-alpha-initiated neutrophil responses and trafficking: novel regulators of a cytokine-chemokine axis relevant to periodontal diseases.
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.
Pouliot
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Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Serhan
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D015847:Interleukin-4 / Q000378:metabolism; D044045:Lipoxins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects*; D010510:Periodontal Diseases / Q000209:etiology / Q000276:immunology; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054426:Chemokine CXCL2; D018925:Chemokines; D002630:Chemotactic Factors; D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D044045:Lipoxins; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D015847:Interleukin-4; D001241:Aspirin