Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes.
Lipoxin A(4) (LXA(4)) and aspirin-triggered 15-epi-LXA(4) (ATL) are emerging as endogenous braking signals for neutrophil-mediated tissue injury. Recent studies indicate that peroxynitrite (ONOO(-)) may function as an intracellular signal for the production of IL-8, a potent proinflammatory cytokine in human leukocytes. In this study, we evaluated the impact of the metabolically stable analogues of LXA(4)/ATL on lipopolysaccharide (LPS)-induced ONOO(-) formation and ONOO(-)-mediated IL-8 gene expression in human leukocytes. At nanomolar concentrations, LXA(4) analogues markedly reduced LPS-stimulated superoxide formation, evoked increases in intracellular diamino-fluorescein fluorescence (an indicator of NO formation), and consequently reduced ONOO(-) formation in isolated neutrophils, as well as in neutrophils, monocytes, and lymphocytes, in whole blood. LXA(4)/ATL analogues attenuated nuclear accumulation of activator protein-1 and nuclear factor-kappaB in both polymorphonuclear and mononuclear leukocytes and inhibited IL-8 mRNA expression and IL-8 release by 50-65% in response to LPS. The LXA(4) inhibitory responses were concentration dependent and were not shared by 15-deoxy-LXA(4). None of the LXA(4) analogues studied affected neutrophil survival, nor reversed the apoptosis delaying action of LPS in neutrophils. In addition, LXA(4) analogues had no significant effect on exogenous ONOO(-)-induced IL-8 gene and protein expression. These findings suggest that by attenuating ONOO(-) formation, LXA(4) and ATL can oppose ONOO(-) signaling in leukocytes and provide a rationale for using stable synthetic analogues as antiinflammatory compounds in vivo.
József
Levente
L
Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, QC, Canada H1T 2M4.
Zouki
Christine
C
Petasis
Nicos A
NA
Serhan
Charles N
CN
Filep
János G
JG
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology*; D002467:Cell Nucleus; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007962:Leukocytes / Q000378:metabolism; D044045:Lipoxins; D008214:Lymphocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006893:Hydroxyeicosatetraenoic Acids; D016209:Interleukin-8; D044045:Lipoxins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C040527:lipoxin A4; D013481:Superoxides; D030421:Peroxynitrous Acid; D012260:Ribonucleases; D001241:Aspirin