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Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes

Authors
  • Levente József
  • Christine Zouki
  • Nicos A. Petasis
  • Charles N. Serhan
  • János G. Filep
Publisher
The National Academy of Sciences
Publication Date
Sep 16, 2002
Source
PMC
Keywords
Disciplines
  • Biology
License
Unknown

Abstract

Lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 (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 LXA4/ATL on lipopolysaccharide (LPS)-induced ONOO− formation and ONOO−-mediated IL-8 gene expression in human leukocytes. At nanomolar concentrations, LXA4 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. LXA4/ATL analogues attenuated nuclear accumulation of activator protein-1 and nuclear factor-κB in both polymorphonuclear and mononuclear leukocytes and inhibited IL-8 mRNA expression and IL-8 release by 50–65% in response to LPS. The LXA4 inhibitory responses were concentration dependent and were not shared by 15-deoxy-LXA4. None of the LXA4 analogues studied affected neutrophil survival, nor reversed the apoptosis delaying action of LPS in neutrophils. In addition, LXA4 analogues had no significant effect on exogenous ONOO−-induced IL-8 gene and protein expression. These findings suggest that by attenuating ONOO− formation, LXA4 and ATL can oppose ONOO− signaling in leukocytes and provide a rationale for using stable synthetic analogues as antiinflammatory compounds in vivo.

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