Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT
Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT
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DOI：
10.1006/cimm.1996.0109
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发表时间：
1996-05-01
影响因子：
4.3
通讯作者：
Chen, M
中科院分区：
文献类型：
--
作者：
Whisler, RL;Liu, BQ;Chen, M
虽然转录因子AP-1和活化T细胞核因子（NF-AT）对于IL-2的正常诱导是重要的，但是不知道活化的人T细胞产生IL-2的年龄相关性下降是否可能与转录调节蛋白的异常有关。在用PHA、PHA加PMA、交联抗CDS mAb OKT 3加PMA或PMA加离子霉素刺激的培养物中测量来自老年人（平均78岁）和年轻人（平均37岁）的T细胞的IL-2产生。从12个老年人中的7个的细胞培养物中观察到响应于不同刺激的IL-2产生的实质性减少，而由来自其他老年人的受刺激的T细胞产生的IL-2水平与针对年轻受试者的受刺激的T细胞观察到的水平相当。通过电泳DNA迁移率变动分析的核提取物的分析表明，减少IL-2的产生由刺激的T细胞的老年人是密切相关的AP-1和NF-AT的激活损伤。相比之下，来自具有正常IL-2产生水平的老年受试者的T细胞表现出AP-1和NF-AT的正常活化。此外，分析NF-AT的正常组分的竞争实验的结果表明，刺激依赖性NF-AT复合物中与年龄相关的减少对应于由c-Fos/c-Jun AP-1组成的缓慢迁移复合物。在某些老年人的T细胞中，NF κ B的静息和刺激水平降低;然而，NF κ B的改变与IL-2表达的变化无关。因此，这些结果表明，AP-1和NF-AT活化中的年龄相关损伤与IL-2表达降低密切相关，并进一步表明，对诱导转录活性c-Fos/c-Jun AP-1重要的信号传导途径的异常可能导致NF-AT活化受损。(C)出版社：Academic Press，Inc.
Although transcriptional factors AP-1 and nuclear factor of activated T cells (NF-AT) are important for the normal induction of IL-2, it is unknown if the age-related decline in IL-2 production by activated human T cells may be associated with aberrancies in transcriptional regulatory proteins, In the current studies, IL-2 production by T cells from elderly (mean 78 years) and young (mean 37 years) humans was measured in cultures stimulated with PHA, PHA plus PMA, crosslinked anti-CDS mAb OKT3 plus PMA, or PMA plus ionomycin. Substantial decreases of IL-2 production were observed for cell cultures from 7 of 12 elderly individuals in response to the different stimuli, whereas the levels of IL-2 produced by stimulated T cells from other elderly individuals were equivalent to those observed for stimulated T cells of young subjects. Analyses of nuclear extracts by electrophoretic DNA mobility shift assays showed that decreased IL-2 production by stimulated T cells of elderly individuals was closely associated with impairments in the activation of both AP-1 and NF-AT. By contrast, T cells from elderly subjects with normal levels of IL-2 production exhibited normal activation of AP-1 and NF-AT, In addition, the results of competition experiments analyzing the normal components of NF-AT showed that the age-related reductions in stimulus-dependent NF-AT complexes corresponded to the slow migrating complexes that were composed of c-Fos/c-Jun AP-1. The resting and stimulated levels of NF kappa B were reduced in T cells from certain elderly individuals; however, alterations of NF kappa B did not correlate with changes in IL-2 expression. Thus, these results show that age-related impairments in the activation of AP-1 and NF-AT are closely associated with decreased expression of IL-2 and further suggest that aberrancies in the signaling pathways important for the induction of transcriptionally active c-Fos/c-Jun AP-1 may contribute to the impaired activation of NF-AT. (C) 1996 Academic Press, Inc.