Fortin Carl F, Larbi Anis, Dupuis Gilles, Lesur Olivier, Fülöp Tamàs
Department of Medicine, Research Center on Aging, Laboratory of Biogerontology, Sherbrooke Geriatric University Institute, 1036, rue Belvèdere sud, J1H 4C4 Sherbrooke, QC, Canada.
Biogerontology. 2007 Apr;8(2):173-87. doi: 10.1007/s10522-006-9067-1. Epub 2006 Nov 4.
Polymorphonuclear neutrophils (PMN) are the first cells to be recruited to the site of tissular aggression. They have a short-life span and die by spontaneous apoptosis. However, their life span and functional activities can be extended in vitro by a number of proinflammatory cytokines, including the granulocyte-macrophage colony stimulating factor (GM-CSF). We have reported that the protective effect of GM-CSF did not occur in PMN of elderly subjects. Data reported here showed that this difference was not due to a change in the expression of the GM-CSF receptor in the PMN of elderly individuals compared to young subjects. Furthermore, we showed here that GM-CSF activated the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway and this activation appeared to be maintained for an extended period of time (18 h) playing an important role in the GM-CSF induced delayed PMN apoptosis. In marked contrast, GM-CSF had no effects on Jak2 activation in PMN of elderly individuals. We found that an inhibitor of Jak2 activation (AG490) abolished the protective effect of GM-CSF in PMN from young donors, however had no effect in PMN of elderly subjects. GM-CSF induced a transient activation of STAT3 and STAT5 in PMN of young donors but failed to activate to the same extent these signal transducers in PMN of elderly donors. The levels of proCaspase-3 were reduced in PMN of young donors treated with GM-CSF for 18 h but remained unchanged in PMN of elderly subjects treated under the same conditions compared to the untreated PMN. Our data are consistent with the interpretation that, at least in part (1) the protective effect of GM-CSF against apoptosis results from the activation of the Jak/STAT pathway and (2) decreased rescue from apoptosis in PMN of elderly is related to a failure of GM-CSF to activate this pathway in these cells.
多形核中性粒细胞（PMN）是最早被招募到组织损伤部位的细胞。它们寿命较短，会通过自发凋亡而死亡。然而，它们的寿命和功能活性可以在体外通过多种促炎细胞因子得到延长，包括粒细胞-巨噬细胞集落刺激因子（GM-CSF）。我们曾报道GM-CSF的保护作用在老年受试者的PMN中并未出现。此处报道的数据表明，与年轻受试者相比，这种差异并非由于老年个体PMN中GM-CSF受体表达的改变所致。此外，我们在此表明GM-CSF激活了Janus激酶/信号转导子和转录激活子（Jak/STAT）途径，并且这种激活似乎会持续较长时间（18小时），在GM-CSF诱导的PMN延迟凋亡中发挥重要作用。与之形成显著对比的是，GM-CSF对老年个体PMN中的Jak2激活没有影响。我们发现Jak2激活抑制剂（AG490）消除了GM-CSF对年轻供体PMN的保护作用，但对老年受试者的PMN没有影响。GM-CSF在年轻供体的PMN中诱导了STAT3和STAT5的短暂激活，但在老年供体的PMN中未能以相同程度激活这些信号转导子。与未处理的PMN相比，用GM-CSF处理18小时的年轻供体PMN中前半胱天冬酶-3的水平降低，但在相同条件下处理的老年受试者PMN中该水平保持不变。我们的数据符合以下解释：至少部分地（1）GM-CSF对凋亡的保护作用源于Jak/STAT途径的激活，以及（2）老年PMN中凋亡挽救减少与GM-CSF未能在这些细胞中激活该途径有关。
