A synthetic analog of 15-epi-lipoxin A4 inhibits human monocyte apoptosis: involvement of ERK-2 and PI3-kinase.
Human monocytes play a central function in several steps of the immune response and the process involved in regulating their survival are critical to population control. Lipoxins are lipid mediators and members of the eicosanoid family that exhibit selective stimulatory but nonphlogistic activities in mononuclear cells. In this study, we investigated the effects of 15-epi-16-(para-fluoro)phenoxy-LXA(4) (ATL-1), a synthetic analog of 15-epi-lipoxin A(4), in human monocytes survival and apoptosis. ATL-1 concentration-dependently increased monocyte survival, as a consequence of cell apoptosis reduction by the analog. Treatment of these cells with PD98059 or LY294002 blocked ATL-1 effects, indicating the involvement of ERK-2 and PI3-K, both pathways associated with cell survival. Confirming the activation of these pathways, we demonstrated an increase in ERK-2 nuclear translocation and Akt phosphorylation. Furthermore, we showed that ATL-1 inhibits Bax translocation to the mitochondria. These results confirm a cytoprotective effect of lipoxins in monocytes and might contribute to the elucidation of the mechanisms associated with the resolution phase of the inflammatory process in different pathophysiological events.
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Departamento de Farmacologia e Psicobiologia, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87 fundos, 5(o) andar, sala 2 - Vila Isabel, Rio de Janeiro 20551-030, Brazil.
Niconi-de-Almeida
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Y
da-Fé
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Barja-Fidalgo
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Fierro
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D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D044045:Lipoxins / Q000737:chemistry* / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C447621:16-(4-fluorophenoxy)lipoxin A4; D002867:Chromones; D005419:Flavonoids; D044045:Lipoxins; D009025:Morpholines; D043562:Receptors, G-Protein-Coupled; D051028:bcl-2-Associated X Protein; C040527:lipoxin A4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one