The role of the MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging.
The role of the MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging.
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DOI：
10.1186/1742-4933-2-6
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发表时间：
2005-03-02
期刊：
影响因子：
--
通讯作者：
Fulop T Jr
中科院分区：
文献类型：
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作者：
Larbi A;Douziech N;Fortin C;Linteau A;Dupuis G;Fulop T Jr
中性粒细胞代表抵御攻击的第一道防线。中性粒细胞的程序性死亡被促炎刺激延迟，以确保炎症在时间和地点得到适当的解决。促炎刺激物包括粒细胞巨噬细胞集落刺激因子（GM-CSF）。最近，我们已经证明，虽然老年受试者中的中性粒细胞与年轻受试者相比具有相同的自发性凋亡，但GM-CSF诱导的延迟性细胞凋亡显着减少。本研究探讨 GM-CSF 对 MAPK 刺激的改变是否在老年受试者 PMN 细胞凋亡的挽救减弱中发挥作用。从满足 SENIEUR 方案的健康年轻和老年捐赠者中分离出中性粒细胞。用 GM-CSF 和 MAPK 激酶途径抑制剂刺激中性粒细胞。本研究进行了凋亡承诺、信号分子磷酸化、caspase-3 活性以及促凋亡和抗凋亡分子的表达。使用学生的独立均值双尾 t 检验分析数据。除非另有说明，显着性设定为 p ≤ 0.05。在本文中，我们提出证据表明，在 GM-CSF 刺激下，老年受试者的 PMN 中 p42/p44 MAPK 激活发生改变，这在减少老年人 PMN 凋亡延迟方面发挥了作用。我们还发现，p38 MAPK 在任何年龄组 PMN 的 GM-CSF 延迟凋亡中均不发挥作用，但参与自发性细胞凋亡。我们的结果还表明，p42/p44 MAPK 激活的改变导致 GM-CSF 无法降低老年受试者 PMN 中的 caspase-3 激活。此外，GM-CSF通过调节年轻受试者PMN中的bcl-2家族成员Bax和Bcl-xL将促凋亡表型转化为抗凋亡表型，而这在老年人PMN中不会发生。然而，这种调制似乎与 MAPK 无关。我们的结果表明，p42/p44 MAPK 激活的改变有助于 GM-CSF 诱导老年受试者中 PMN 免于凋亡的拯救减少。老年受试者中性粒细胞中 MAPK 激活的调节可能有助于随着衰老恢复中性粒细胞的功能。
Neutrophils represent the first line of defence against aggressions. The programmed death of neutrophils is delayed by pro-inflammatory stimuli to ensure a proper resolution of the inflammation in time and place. The pro-inflammatory stimuli include granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, we have demonstrated that although neutrophils have an identical spontaneous apoptosis in elderly subjects compared to that in young subjects, the GM-CSF-induced delayed apoptosis is markedly diminished. The present study investigates whether an alteration of the GM-CSF stimulation of MAPKs play a role in the diminished rescue from apoptosis of PMN of elderly subjects. Neutrophils were separated from healthy young and elderly donors satisfying the SENIEUR protocol. Neutrophils were stimulated with GM-CSF and inhibitors of the MAPKinase pathway. Apoptosis commitment, phosphorylation of signaling molecules, caspase-3 activities as well as expression of pro- and anti-apoptotic molecules were performed in this study. Data were analyzed using Student's two-tailed t-test for independent means. Significance was set for p ≤ 0.05 unless stated otherwise. In this paper we present evidence that an alteration in the p42/p44 MAPK activation occurs in PMN of elderly subjects under GM-CSF stimulation and this plays a role in the decreased delay of apoptosis of PMN in elderly. We also show that p38 MAPK does not play a role in GM-CSF delayed apoptosis in PMN of any age-groups, while it participates to the spontaneous apoptosis. Our results also show that the alteration of the p42/p44 MAPK activation contributes to the inability of GM-CSF to decrease the caspase-3 activation in PMN of elderly subjects. Moreover, GM-CSF converts the pro-apoptotic phenotype to an anti-apoptotic phenotype by modulating the bcl-2 family members Bax and Bcl-xL in PMN of young subjects, while this does not occur in PMN of elderly. However, this modulation seems MAPK independent. Our results show that the alteration of p42/p44 MAPK activation contributes to the GM-CSF induced decreased PMN rescue from apoptosis in elderly subjects. The modulation of MAPK activation in PMN of elderly subjects might help to restore the functionality of PMN with aging.