Lipoxin A(4) metabolites/analogues from two commercial sources have no effects on TNF-alpha-mediated priming or activation through the neutrophil formyl peptide receptors.
The eicosanoid lipoxin A(4) (LXA(4)) is a potent anti-inflammatory mediator in many in vivo experimental models, and it has been proposed that the effects of this molecule are mediated through binding to FPR2 (also termed FPRL1 or ALXR), a member of the formyl peptide receptor family. Research has shown that LXA(4) inhibits neutrophil function, which has been suggested to be an important mechanism in the anti-inflammatory activity of this lipoxin. However, experiments demonstrating such an impact of LXA(4) have not always been convincing. In this study, we examined the influence of metabolically stable LXA(4) analogues on the biological activities induced by a previously characterized FPR2 agonist (WKYMWM) and a commonly used FPR1 agonist (fMLF). We also investigated the analogues regarding their direct effect on TNFalpha-mediated neutrophil mobilization of the complement receptor 3 (CR3) and their indirect effect on cytokine-dependent priming of the cells. The LXA(4) analogues we used came from two commercial sources. In our experiments, they did not induce any direct neutrophil response, nor did they affect the increase in the number of CR3 molecules on the neutrophil surface or the primed response. Therefore, we conclude that these LXA(4) analogues do not have an impact on TNF-alpha induced signalling in neutrophils. We also applied a recently described technique that has proven to be a valuable tool for identifying selective FPR1 and FPR2 agonists and antagonists. We found that the lipoxin analogues did not induce any changes in the neutrophil response, which implies that LXA(4) does not act through FPR2 in these cells.
Forsman
H
H
Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
Dahlgren
C
C
D020013:Calcium Signaling / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D044045:Lipoxins / Q000378:metabolism / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D044067:Receptors, Lipoxin / Q000819:agonists; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D006538:Heptanoic Acids; D044045:Lipoxins; D016177:Macrophage-1 Antigen; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C113617:Trp-Lys-Tyr-Met-Val-Met; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases