A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils
A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils
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DOI：
10.1096/fj.02-0941fje
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发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
Perretti, M
中科院分区：
文献类型：
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作者：
Solito, E;Kamal, A;Perretti, M
糖皮质激素诱导蛋白膜联蛋白（ANXA）1是一种下调宿主反应的抗炎介质。内源性地，ANXA 1从粘附的多形核中性粒细胞（PMN）大量释放，并结合到它们的细胞表面以抑制它们外渗到发炎组织中。本研究探讨了外源性ANXA 1对体外培养的人中性粒细胞几种功能的影响。将0.1-1 μ人重组ANXA 1添加到PMN中引起细胞内Ca 2+浓度的快速和短暂变化，其被Ca 2+通道抑制剂SKF-96365阻断。虽然ANXA 1并不影响氧化剂的产生，只有最低限度地影响中性粒细胞的趋化特性，ANXA 1促进的钙离子内流与两个重要的功能效应：脱落的L-选择素和加速中性粒细胞凋亡。使用三种不同的技术程序，即细胞周期、Hoechst染色和ANXA 5结合测定，证实了后一种效应。ANXA 1诱导的PMN凋亡对L-选择素脱落抑制剂不敏感，而它似乎与促凋亡细胞内介质BAD的去磷酸化有关。总之，外源性ANXA 1对人PMN具有选择性作用。我们认为，这里报道的新的促凋亡作用可能是ANXA 1介导的急性炎症反应的一部分。
The glucocorticoid-inducible protein annexin (ANXA) 1 is an anti-inflammatory mediator that down-regulates the host response. Endogenously, ANXA1 is released in large amounts from adherent polymorphonuclear neutrophils (PMN) and binds to their cell surface to inhibit their extravasation into inflamed tissues. The present study determined the effects of exogenous ANXA1 on several functions of human PMN in vitro. Addition of 0.1-1 mu human recombinant ANXA1 to the PMN provoked rapid and transient changes in intracellular Ca2+ concentrations that were blocked by the Ca2+ channel inhibitor SKF-96365. Although ANXA1 did not affect oxidant production and only minimally affected PMN chemotactic properties, the ANXA1-promoted Ca2+ influx was associated with two important functional effects: shedding of L-selectin and acceleration of PMN apoptosis. The latter effect was confirmed using three distinct technical procedures, namely, cell cycle, Hoechst staining, and ANXA5 binding assay. ANXA1-induced PMN apoptosis was insensitive to inhibitors of L-selectin shedding, whereas it appeared to be associated with dephosphorylation of the proapoptotic intracellular mediator BAD. In conclusion, exogenous ANXA1 displayed selective actions on human PMN. We propose that the new proapoptotic effect reported here may be part of the spectrum of ANXA1-mediated events involved in the resolution of acute inflammation.