Ponnappan Subramaniam, Uken-Trebilcock Gina, Lindquist Michael, Ponnappan Usha
Department of Geriatrics, University of Arkansas for Medical Sciences, Medical research, CAVHS, GC 143, 151LR/VA, 4300 West 7th, Little Rock, AR 72205, USA.
Exp Gerontol. 2004 Apr;39(4):559-66. doi: 10.1016/j.exger.2003.12.012.
NFkappaB induction and gene regulation are compromised in T lymphocytes during aging. This has been attributed to altered proteasomal function resulting in decreased ubiquitin-mediated degradation of IkappaBalpha. However, little is known about the impact of aging on the mechanisms that lead to the release of active NFkappaB employing pro-oxidant pathways. Oxidant-mediated activation of NFkappaB has been previously shown to involve proteasome independent mechanisms and hence may be an important alternate conduit to the induction of this central transcription factor in aging. Employing H(2)O(2) and pervanadate we not only demonstrate lowered tyrosine phosphorylation of IkappaBalpha, but also compromised induction of nuclear NFkappaB in T cells from the elderly. Lowered tyrosine phosphorylation of IkappaBalpha may be due to a decrease in activity of p56(lck) and ZAP-70, since treatment with piceatannol, an inhibitor of syk and src family kinases, mimics age associated decline in tyrosine phosphorylation of IkappaBalpha in T cells from young donors. Thus, alternate pathways of NFkappaB induction are also impaired in T cells from the elderly and may underlie immune-deficit accompanying aging.
衰老过程中，T淋巴细胞中的核因子κB（NFκB）诱导及基因调控受损。这归因于蛋白酶体功能改变，导致IkappaBalpha的泛素介导降解减少。然而，关于衰老对通过促氧化途径导致活性NFκB释放的机制的影响知之甚少。先前已表明，氧化剂介导的NFκB激活涉及蛋白酶体非依赖机制，因此可能是衰老过程中诱导这一核心转录因子的重要替代途径。使用过氧化氢（H₂O₂）和过氧钒酸盐，我们不仅证明了IkappaBalpha的酪氨酸磷酸化降低，还证明了老年人T细胞中核NFκB的诱导受损。IkappaBalpha酪氨酸磷酸化降低可能是由于p56(lck)和ZAP-70活性降低，因为用白藜芦醇（一种syk和src家族激酶抑制剂）处理可模拟年轻供体T细胞中与年龄相关的IkappaBalpha酪氨酸磷酸化下降。因此，老年人T细胞中NFκB诱导的替代途径也受损，这可能是衰老伴随的免疫缺陷的基础。
