Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice
Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice
复制标题
DOI：
10.4049/jimmunol.166.4.2617
复制
发表时间：
2001-02-15
影响因子：
4.4
通讯作者：
Zwollo, P
中科院分区：
文献类型：
--
作者：
Anspach, J;Poulsen, G;Zwollo, P
衰老与体液免疫应答的内在变化有关，这可能导致自身免疫性疾病和致病易感性的增加。转录因子Pax-5是B细胞发育的关键调节因子。Pax-5a/B细胞特异性激活蛋白和选择性剪接的同种型Pax-Sd可能在转录调控中具有相反的功能，这是由于Pax-Sd中缺乏反式激活结构域。为了研究衰老过程中发生的B细胞特异性变化，我们研究了年轻和老年小鼠成熟B细胞中Pax-Sa和Sd的表达模式。RNA酶保护试验显示两个年龄组的转录模式相似，表明衰老对任一亚型的转录起始或选择性剪接没有影响。相反，在体外老化B细胞中观察到Pax-Sa蛋白而非Pax-Sd蛋白的DNA结合活性显著降低，而Western印迹分析显示两个年龄组中存在相似水平的Pax-Sa和Sd蛋白。观察到的Pax-Sa结合活性的降低与衰老B细胞中两种Pax-5靶基因表达的变化相关。已知在成熟B细胞中受Pax-Sa抑制的IG J链和IG μ分泌形式的表达在衰老小鼠的B细胞中增加。我们的研究表明，与衰老表型相关的变化会引起Pax-Sa的翻译后修饰，但不会引起Pax-Sd的翻译后修饰，这可能会导致老年小鼠的异常B细胞表型，与J链水平升高和IgM分泌有关。
Aging has been associated with intrinsic changes of the humoral immune response, which may lead to an increased occurrence of autoimmune disorders and pathogenic susceptibility. The transcription factor Pax-5 is a key regulator of B cell development. Pax-5a/B cell-specific activator protein and an alternatively spliced isoform, Pax-Sd, may have opposing functions in transcriptional regulation due to the lack of a transactivation domain in Pax-Sd. To study B cell-specific changes that occur during the aging process, we investigated expression patterns of Pax-Sa and Sd in mature B cells of young and aged mice. RNase protection assays showed a similar transcriptional pattern for both age groups that indicates that aging has no affect on transcription initiation or alternative splicing for either isoform, In contrast, a significant reduction in the DNA binding activity of Pax-Sa but not Pax-Sd protein was observed in aged B cells in vitro, while Western blot analyses showed that similar levels of Pax-Sa and Sd proteins were present in both age groups. The observed decrease in Pax-Sa binding activity correlated with changes in expression of two Pax-5 target genes in aged B cells, Expression of the Ig J chain and the secreted form of Ig mu, which are both known to be suppressed by Pax-Sa in mature B cells, were increased in B cells of aged mice, Together, our studies suggest that changes associated with the aging phenotype cause posttranslational modification(s) of Pax-Sa but not Pax-Sd, which may lead to an abnormal B cell phenotype in aged mice, associated with elevated levels of J chain, and secretion of IgM.