Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival
Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival
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DOI：
10.4049/jimmunol.181.5.3027
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发表时间：
2008-09-01
影响因子：
4.4
通讯作者：
Jauberteau, Marie-Odile
中科院分区：
文献类型：
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作者：
Fauchais, Anne-Laure;Lalloue, Fabrice;Jauberteau, Marie-Odile
脑源性神经营养因子(BDNF)是一种主要的神经生长因子，在骨髓瘤细胞中也具有抗凋亡作用。虽然BDNF在B淋巴细胞中的分泌已被描述，但B细胞产生其运输蛋白山梨素的能力此前未见报道。我们研究了在正常和应激培养条件下(血清剥夺、Fas激活或两者结合)，BDNF及其受体、酪氨酸蛋白激酶受体B和p75神经营养因子受体在人前B期、成熟和浆细胞性恶性B细胞系中的表达。血清剥夺可促进BDNF的分泌，并发挥抗细胞凋亡的作用，拮抗抗体的中和实验证明了这一点。同样由B细胞分泌的前体形式-BDNF在应激条件下减少，与BDNF的产生相反。应激条件诱导p75神经营养素受体和酪氨酸蛋白激酶B受体的膜表达，在成熟的B细胞中表达最强，而在正常培养条件下这两种受体都被隔离。通过阻断抗体和小干扰RNA，我们证明BDNF的产生和它的生存功能依赖于山梨素，这是一种调节神经元中神经营养素运输的蛋白质，这是以前在B细胞中没有描述的。因此，在成熟的B细胞系中，BDNF的自分泌产物在应激培养条件下上调，并通过山梨素途径调节细胞凋亡。这可能对阐明恶性B细胞的某些耐药性具有重要意义。此外，原代B淋巴细胞含有山梨素，并在有丝分裂激活后产生BDNF，提示山梨素和BDNF可能也参与了正常B细胞的存活和激活。
Brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is also known to exert an antiapoptotic effect in myeloma cells. Whereas BDNF secretion was described in B lymphocytes, the ability of B cells to produce sortilin, its transport protein, was not previously reported. We studied BDNF production and the expression of its receptors, tyrosine protein kinase receptor B and p75 neurotrophin receptor in the human pre-B, mature, and plasmacytic malignant B cell lines under normal and stress culture conditions (serum deprivation, Fas activation, or their combination). BDNF secretion was enhanced by serum deprivation and exerted an antiapoptotic effect, as demonstrated by neutralization experiments with antagonistic Ab. The precursor form, pro-BDNF, also secreted by B cells, decreases under stress conditions in contrast to BDNF production. Stress conditions induced the membranous expression of p75 neurotrophin receptor and tyrosine protein kinase receptor B, maximal in mature B cells, contrasting with the sequestration of both receptors in normal culture. By blocking Ab and small interfering RNA, we evidenced that BDNF production and its survival function are depending on sortilin, a protein regulating neurotrophin transport in neurons, which was not previously described in B cells. Therefore, in mature B cell lines, an autocrine BDNF production is up-regulated by stress culture conditions and exerts a modulation of apoptosis through the sortilin pathway. This could be of importance to elucidate certain drug resistances of malignant B cells. In addition, primary B lymphocytes contained sortilin and produced BDNF after mitogenic activation, which suggests that sortilin and BDNF might be implicated in the survival and activation of normal B cells also.