Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1alpha-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis.
The impact of lipoxin A4 (LXA4) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-alpha-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-alpha-stimulated superoxide anion generation and IL-1beta release by human polymorphonuclear leukocytes. These LXA4-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-1beta 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-alpha-stimulated leukocyte trafficking, as well as the appearance of both macrophage inflammatory peptide 2 and IL-1beta, while concomitantly stimulating IL-4 in pouch exudates. Together, these results indicate that both LXA4 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 responses.
Hachicha
M
M
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, USA.
Pouliot
M
M
Petasis
N A
NA
Serhan
C N
CN
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics; D015847:Interleukin-4 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D044045:Lipoxins; D008297:Male; D051379:Mice; D015394:Molecular Structure; D015846:Monokines / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054426:Chemokine CXCL2; D018925:Chemokines; D016207:Cytokines; C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D044045:Lipoxins; D015846:Monokines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D013481:Superoxides; D015847:Interleukin-4; D001241:Aspirin