Aminopeptidase N (CD13) regulates tumor necrosis factor-α-induced apoptosis in human neutrophils

被引:31
作者
Cowburn, AS
Sobolewski, A
Reedo, BJ
Deighton, J
Murray, J
Cadwallader, KA
Bradley, JR
Chilvers, ER
机构
[1] Univ Cambridge, Addenbrookes Hosp, Resp Med Div, Dept Med,Sch Clin Med, Cambridge CB2 2QQ, England
[2] Univ Cambridge, Papworth Hosp, Resp Med Div, Dept Med,Sch Clin Med, Cambridge CB2 2QQ, England
[3] Univ Edinburgh, Resp Med Unit, MRC, Ctr Inflammat,Sch Med, Edinburgh EH16 4TJ, Midlothian, Scotland
基金
英国惠康基金;
关键词
D O I
10.1074/jbc.M511277200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor-alpha(TNF alpha) enhances the rate of neutrophil apoptosis at early time points via a mechanism involving both TNF receptor ( TNFR) I and TNFRII. Here we reveal a marked but consistent variation in the magnitude of the pro-apoptotic effect of TNF alpha in neutrophils isolated from healthy donors, and we show that inhibition of cell surface aminopeptidaseN(APN) using actinonin, bestatin, or inhibitory peptides significantly enhanced the efficacy of TNF alpha-induced killing. Notably, an inverse correlation is shown to exist between neutrophil APN activity and the sensitivity of donor cells to TNF alpha-induced apoptosis. Inhibition of cell surface APN appears to interfere with the shedding of TNFRI, and as a consequence results in augmented TNF alpha-induced apoptosis, cell polarization, and TNF alpha-primed, formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst. Of note, actinonin and bestatin had no effect on TNFRII expression under resting or TNF alpha-stimulated conditions and did not alter CXCRI or CXCRII expression. These data suggest significant variation in the activity of APN/CD13 on the cell surface of neutrophils in normal individuals and reveal a novel mechanism whereby APN/CD13 regulates TNF alpha-induced apoptosis via inhibition of TNFRI shedding. This has therapeutic relevance for driving neutrophil apoptosis in vivo.
引用
收藏
页码:12458 / 12467
页数:10
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