A molecular mechanism for TNF-α-mediated downregulation of B cell responses.
A molecular mechanism for TNF-α-mediated downregulation of B cell responses.
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DOI：
10.4049/jimmunol.1003964
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Blomberg BB
中科院分区：
文献类型：
--
作者：
Frasca D;Romero M;Diaz A;Alter-Wolf S;Ratliff M;Landin AM;Riley RL;Blomberg BB
B细胞的类别转换重组（CSR）、活化诱导的胞苷脱氨酶（AID）和E47 mRNA的稳定性随年龄增长而降低。后者至少部分受三曲脯氨酸（TTP）调节，TTP在老化B细胞中增加，也负调节TNF-α。在这里，我们研究了B细胞是否产生TNF-α，这是否随年龄而变化，以及这如何影响它们在刺激时的功能。我们的假设是，在衰老过程中，存在自分泌炎性细胞因子（TNF-α）的反馈机制，其降低AID和CSR的表达。结果表明，老年BALB B/c小鼠未受刺激的B细胞分泌TNF-α mRNA和蛋白的量明显高于青年小鼠的B细胞，但受刺激后，老年B细胞分泌TNF-α mRNA和蛋白的量低于青年小鼠，因此老年B细胞对刺激不敏感。老年B细胞产生的TNF-α增加主要是由于滤泡，而不是B细胞的次要亚群。在LPS刺激前用TNF-α预孵育B细胞可降低年轻和老年B细胞的反应。重要的是，通过在培养的B细胞中加入抗TNF-α抗体恢复了B细胞功能。为了解决分子机制，我们发现在LPS刺激之前，用TNF-α预孵育B细胞，诱导tristetraprolin，一种对CSR至关重要的转录因子E47 mRNA稳定性的生理调节剂。最后，体内给予抗TNF-α能够增加老年卵泡B细胞的功能，但不能增加年轻卵泡B细胞的功能。这些结果表明，新的分子机制，有助于减少抗体反应的老化。
B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID) and stability of E47 mRNA. The latter is regulated at least in part by tristetraprolin (TTP) which is increased in aged B cells and also negatively regulates TNF-α. Here, we investigate whether B cells produce TNF-α, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-α) that lowers the expression of AID and CSR. Our results show that unstimulated B cells from old BALB/c mice make significantly more TNF-α mRNA and protein than B cells from young mice, but after stimulation the old make less than young, thus they are refractory to stimulation. The increase in TNF-α made by old B cells is primarily due to follicular, but not minor subsets of B cells. Pre-incubation of B cells with TNF-α before LPS stimulation decreases both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-α antibody in cultured B cells. To address a molecular mechanism, we found that pre-incubation of B cells with TNF-α, before LPS stimulation, induces tristetraprolin, a physiological regulator of mRNA stability of the transcription factor E47, crucial for CSR. Finally, anti-TNF-α given in vivo was able to increase follicular B cell function in old but not in young follicular B cells. These results suggest new molecular mechanisms which contribute to reduced antibody responses in aging.
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DOI：
10.1016/j.bbrc.2006.05.093
发表时间：
2006-07-21
影响因子：
3.1
作者：
Chen, Yu-Ling;Huang, Ya-Lin;Chang, Ching-Jin
通讯作者：
Chang, Ching-Jin
影响因子：
5.9
作者：
Harris, TB;Ferrucci, L;Wallace, R
通讯作者：
Wallace, R
影响因子：
5.3
作者：
Boehmer, ED;Meehan, MJ;Kovacs, EJ
通讯作者：
Kovacs, EJ
影响因子：
20.3
作者：
Hao, Yi;O'Neill, Patrick;Cancro, Michael P.
通讯作者：
Cancro, Michael P.
影响因子：
20.3
作者：
Ferrucci, L;Corsi, A;Longo, DL
通讯作者：
Longo, DL