Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways.
Lipoxin A(4) (LXA(4)) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA(4) on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA(4) on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA(4) at the concentrations prevailing in the course of resolution of inflammation (nanomolar range) significantly inhibits the apoptosis induced by staurosporine, etoposide and S-nitrosoglutathione or by more pathophysiological stimuli, such as LPS/IFNgamma challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA(4). In addition to this, the synthesis of reactive oxygen species induced by staurosporine was attenuated and antiapoptotic proteins of the Bcl-2 family accumulated in the presence of lipoxin. Analysis of the targets of LXA(4) identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA(4). These data suggest that the LXA(4), released after the recruitment of neutrophils to sites of inflammation, exerts a protective effect on macrophage viability that might contribute to a better resolution of inflammation.
Prieto
P
P
Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
Cuenca
J
J
Través
P G
PG
Fernández-Velasco
M
M
Martín-Sanz
P
P
Boscá
L
L
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C040527:lipoxin A4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019311:Staurosporine