Apoptotic pathways are inhibited by leptin receptor activation in neutrophils.
Leptin regulates food intake as well as metabolic, endocrine, and immune functions. It exerts proliferative and antiapoptotic activities in a variety of cell types, including T cells. Leptin also stimulates macrophages and neutrophils, and its production is increased during inflammation. In this study, we demonstrate that human neutrophils express leptin surface receptors under in vitro and in vivo conditions, and that leptin delays apoptosis of mature neutrophils in vitro. The antiapoptotic effects of leptin were concentration dependent and blocked by an anti-leptin receptor mAb. The efficacy of leptin to block neutrophil apoptosis was similar to G-CSF. Using pharmacological inhibitors, we obtained evidence that leptin initiates a signaling cascade involving PI3K- and MAPK-dependent pathways in neutrophils. Moreover, leptin delayed the cleavage of Bid and Bax, the mitochondrial release of cytochrome c and second mitochondria-derived activator of caspase, as well as the activation of both caspase-8 and caspase-3 in these cells. Taken together, leptin is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in inflammatory diseases.
Bruno
Andreina
A
Department of Pharmacology, University of Bern, Bern, Switzerland.
Conus
Sébastien
S
Schmid
Inès
I
Simon
Hans-Uwe
HU
D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D054411:Receptors, Leptin; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D024101:Mitochondrial Proteins; D019869:Phosphatidylinositol 3-Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C494814:BID protein, human; C412403:DIABLO protein, human; C515448:LEPR protein, human; C505407:CASP3 protein, human