Ponnappan U, Zhong M, Trebilcock G U
Department of Geriatrics, GRECC, University of Arkansas for Medical Sciences, John C. McClellan Memorial Hospital, 4300 W. 7th Street, Little Rock, Arkansas 72205, USA.
Cell Immunol. 1999 Mar 15;192(2):167-74. doi: 10.1006/cimm.1998.1418.
Induction of NFkappaB is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor IkappaBalpha. Analyses of the regulation of IkappaBalpha in TNF-alpha-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of IkappaBalpha in T cells from the elderly. Examination of activation-induced phosphorylation and ubiquitination of IkappaBalpha did not demonstrate any significant age-related alterations. However, examination of proteasome activity in these T cells using fluorogenic peptide assays revealed a significant age-related decline in chymotryptic activity. These results suggest that a decline in proteasome activity results in a failure to fully degrade IkappaBalpha in the elderly. This failure to degrade IkappaBalpha may underlie both the observed decrease in NFkappaB induction and the IL-2 receptor expression in TNF-treated T cells during aging. Thus, decreased proteasome-mediated degradation may be central to immune dysfunction that accompanies aging.
核因子κB（NFκB）的诱导是一个高度受调控的过程，需要对胞质抑制剂κBα（IkappaBalpha）进行磷酸化、泛素化以及蛋白酶体介导的降解。对年轻和老年供体的肿瘤坏死因子α（TNF-α）处理的T淋巴细胞中IkappaBalpha的调控分析显示，老年T细胞中IkappaBalpha的降解严重受损。对IkappaBalpha的激活诱导磷酸化和泛素化的检查未显示任何与年龄相关的显著变化。然而，使用荧光肽测定法对这些T细胞中的蛋白酶体活性进行检查发现，胰凝乳蛋白酶活性存在显著的年龄相关下降。这些结果表明，蛋白酶体活性下降导致老年人中IkappaBalpha无法完全降解。这种无法降解IkappaBalpha的情况可能是衰老过程中TNF处理的T细胞中观察到的NFκB诱导减少和白细胞介素-2受体表达减少的基础。因此，蛋白酶体介导的降解减少可能是衰老伴随的免疫功能障碍的核心。
