Senescent B lymphopoiesis is balanced in suppressive homeostasis:: Decrease in interleukin-7 and transforming growth factor-β levels in stromal cells of senescence-accelerated mice
Senescent B lymphopoiesis is balanced in suppressive homeostasis:: Decrease in interleukin-7 and transforming growth factor-β levels in stromal cells of senescence-accelerated mice
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DOI：
10.1177/153537020422900607
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发表时间：
2004-06-01
影响因子：
3.2
通讯作者：
Inoue, T
中科院分区：
文献类型：
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作者：
Tsuboi, I;Morimoto, K;Inoue, T
衰老过程中B细胞群的抑制被认为是由于白细胞介素-7 （IL-7）的产生和对IL-7的反应受到抑制；然而，转化生长因子- β (tgf - β)的上调被发现有助于B细胞抑制。为了探讨衰老过程中IL-7与tgf - β相互作用的抑制机制，本研究采用衰老小鼠模型衰老加速小鼠（SAMs）来阐明衰老过程中B淋巴生成抑制的机制。与常规衰老小鼠相似，SAMs显示il -7应答的B细胞祖细胞（即股骨髓中集落形成单位前B [CFU-pre-B]细胞[BM]）数量减少。作者建立的B淋巴细胞和基质细胞共培养系统显示，BM细胞与衰老基质细胞共培养获得的cfu -前B细胞数量明显低于与年轻基质细胞共培养。有趣的是，从衰老基质中收获的细胞和从没有基质细胞的对照培养中收获的细胞数量高于从年轻基质中收获的细胞，这意味着改变的衰老基质细胞无法维持干细胞室的自我更新。由于tgf - β被认为会抑制pro-B/pre-B细胞的增殖能力，我们在富含pro-B/pre-B细胞的共培养系统中加入了一种中和性抗tgf - β抗体，以确定这种抑制是否可以恢复。然而，出乎意料的是，与与年轻基质细胞共培养相比，BM细胞与衰老基质细胞共培养未观察到任何挽救，CFU-pre-B细胞数量保持不变，实质上是CFU-pre-B细胞数量增加（5杯/ml P < 0.001）。此外，采用酶联免疫吸收法测定衰老基质细胞上清中tgf - β蛋白水平，但令人惊讶的是，tgf - β浓度明显低于培养的年轻基质细胞。因此，tgf - β活性被认为在衰老基质中尤其下降，这意味着B淋巴生成的衰老抑制与继发性B淋巴细胞减少之间存在明显差异。另一方面，在增殖信号方面，新分离的BM细胞中IL-7基因的表达水平随着年龄的增长而显著下降。因此，在衰老的基质中，增殖信号的加速和抑制性信号的减速都可能被改变和减弱（即同源抑制）。
The suppression of the B cell population during senescence has been considered to be due to the suppression of interleukin-7 (IL-7) production and responsiveness to IL-7; however, the upregulation of transforming growth factor-beta (TGF-beta) was found to contribute to B cell suppression. To investigate the mechanism of this suppression based on the interrelationship between IL-7 and TGF-beta during senescence, senescence-accelerated mice (SAMs), the mouse model of aging, were used in this study to elucidate the mechanisms of B lymphopoietic suppression during aging. Similar to regular senescent mice, SAMs showed a decrease in the number of IL-7-responding B cell progenitors (i.e., colony-forming unit pre-B [CFU-pre-B] cells in the femoral bone marrow [BM]). A co-culture system of B lymphocytes and stromal cells that the authors established showed a significantly lower number of CFU-pre-B cells harvested when BM cells were co-cultured with senescent stromal cells than when they were co-cultured with young stromal cells. Interestingly, cells harvested from a senescent stroma and those from the control culture without stromal cells were higher in number than those harvested from a young stroma, thereby implying that an altered senescent stromal cell is unable to maintain self-renewal of the stem cell compartment. Because TGF-beta is supposed to suppress the proliferative capacity of pro-B/pre-B cells, we added a neutralizing anti-TGF-beta antibody to the co-culture system with a pro-B/pre-B cell-rich population to determine whether such suppression may be rescued. However, unexpectedly, any rescue was not observed and the number of CFU-pre-B cells remained unchanged when BM cells were co-cultured with senescent stromal cells compared with the co-culture with young stromal cells, which essentially showed an increase in the number of CFU-pre-B cells (P < 0.001 in 5 mug/ml). Furthermore, TGF-beta protein level in the supernatant of cultured senescent stroma cells was evaluated by enzyme-linked immunoabsorbent assay, but surprisingly, it was found that TGF-beta concentration was significantly lower than that of cultured young stromal cells. Thus, TGF-beta activity was assumed to decline particularly in a senescent stroma, which means a distinct difference between the senescent suppression of B lymphopoiesis and secondary B lymphocytopenia. Concerning proliferative signaling, on the other hand, the level of IL-7 gene expression in cells from freshly isolated BM decreased significantly with age. Therefore, the acceleration of proliferative signaling and the deceleration of suppressive signaling may both be altered and weakened in a senescent stroma (i.e., homeosupression).