Apoptotic pathways are inhibited by leptin receptor activation in neutrophils

被引:157
作者
Bruno, A [1 ]
Conus, S [1 ]
Schmid, LS [1 ]
Simon, HU [1 ]
机构
[1] Univ Bern, Dept Pharmacol, CH-3010 Bern, Switzerland
关键词
D O I
10.4049/jimmunol.174.12.8090
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:8090 / 8096
页数:7
相关论文
共 45 条
[1]   Calpain-1 regulates Bax and subsequent Smac-dependent caspase-3 activation in neutrophil apoptosis [J].
Altznauer, F ;
Conus, S ;
Cavalli, A ;
Folkers, G ;
Simon, HU .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (07) :5947-5957
[2]   Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations [J].
Altznauer, F ;
von Gunten, S ;
Späth, P ;
Simon, HU .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2003, 112 (06) :1185-1190
[3]   Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils [J].
Altznauer, F ;
Martinelli, S ;
Yousefi, S ;
Thürig, C ;
Schmid, I ;
Conway, EM ;
Schöni, MH ;
Vogt, P ;
Mueller, C ;
Fey, MF ;
Zangemeister-Wittke, U ;
Simon, HU .
JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (10) :1343-1354
[4]  
Aoshiba K, 1999, J IMMUNOL, V162, P1692
[5]   Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway [J].
Baumann, R ;
Casaulta, C ;
Simon, D ;
Conus, S ;
Yousefi, S ;
Simon, HU .
FASEB JOURNAL, 2003, 17 (15) :2221-2230
[6]   Functional expression of CD134 by neutrophils [J].
Baumann, R ;
Yousefi, S ;
Simon, D ;
Russmann, S ;
Mueller, C ;
Simon, HU .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2004, 34 (08) :2268-2275
[7]   A role for leptin and its cognate receptor in hematopoiesis [J].
Bennett, BD ;
Solar, GP ;
Yuan, JQ ;
Mathias, J ;
Thomas, GR ;
Matthews, W .
CURRENT BIOLOGY, 1996, 6 (09) :1170-1180
[8]   Divergent signaling capacities of the long and short isoforms of the leptin receptor [J].
Bjorbaek, C ;
Uotani, S ;
da Silva, B ;
Flier, JS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (51) :32686-32695
[9]   Plasma leptin levels are increased in survivors of acute sepsis: Associated loss of diurnal rhythm in cortisol and leptin secretion [J].
Bornstein, SR ;
Licinio, J ;
Tauchnitz, R ;
Engelmann, L ;
Negrao, AB ;
Gold, P ;
Chrousos, GP .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1998, 83 (01) :280-283
[10]  
Caldefie-Chezet F, 2001, J LEUKOCYTE BIOL, V69, P414