TNF-α affects human cortical neural progenitor cell differentiation through the autocrine secretion of leukemia inhibitory factor.
TNF-α affects human cortical neural progenitor cell differentiation through the autocrine secretion of leukemia inhibitory factor.
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DOI：
10.1371/journal.pone.0050783
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Peng H
中科院分区：
文献类型：
--
作者：
Lan X;Chen Q;Wang Y;Jia B;Sun L;Zheng J;Peng H
促炎细胞因子肿瘤坏死因子-α（TNF-α）是脑中免疫应答的关键效应物，其参与多种急性和慢性神经退行性疾病的发病机制。越来越多的证据表明，TNF-α负性调节胚胎和成体神经发生。然而，TNF-α对人神经前体细胞（NPC）命运决定的影响很少被研究。我们前期的研究表明，重组TNF-α通过STAT 3（signal transducer and activator of transcription 3）途径促进人NPC的星形胶质细胞生成并抑制其神经发生。在本研究中，我们进一步阐明了TNF-α诱导星形胶质细胞生成的具体机制。我们发现TNF-α在延迟的时间点（6 h和24 h）激活STAT 3，而从TNF-α处理的NPC收集的条件培养基诱导立即激活STAT 3。这些数据表明TNF-α在STAT 3激活和随后的NPC分化中起间接作用。此外，我们发现TNF-α在人NPC中诱导了大量的IL-6家族细胞因子，包括白血病抑制因子（LIF）和白细胞介素6（IL-6）。TNF-α诱导的STAT 3磷酸化和星形胶质细胞生成被LIF中和抗体消除，但IL-6没有，揭示了LIF自分泌在TNF-α诱导的STAT 3激活和星形胶质细胞生成中的关键作用。这项研究产生了重要的数据，阐明了TNF-α在神经发生中的作用，并可能为脑炎症的新治疗策略提供见解。
Proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is a crucial effector of immune responses in the brain that participates in the pathogenesis of several acute and chronic neurodegenerative disorders. Accumulating evidence has suggested that TNF-α negatively regulates embryonic and adult neurogenesis. However, the effect of TNF-α on cell fate decision in human neural progenitor cells (NPCs) has rarely been studied. Our previous studies have shown that recombinant TNF-α enhances astrogliogenesis and inhibits neurogenesis of human NPCs through the STAT3 (signal transducer and activator of transcription 3) pathway. In the current study, we further elucidated the specific mechanism involved in TNF-α-induced astrogliogenesis. We found that TNF-α activated STAT3 at delayed time points (6 h and 24 h), whereas conditioned medium collected from TNF-α-treated NPCs induced an immediate STAT3 activation. These data suggest TNF-α plays an indirect role on STAT3 activation and the subsequent NPC differentiation. Further, we showed that TNF-α induced abundant amounts of the IL-6 family cytokines, including Leukemia inhibitory factor (LIF) and Interleukin 6 (IL-6), in human NPCs. TNF-α-induced STAT3 phosphorylation and astrogliogenesis were abrogated by the addition of neutralizing antibody for LIF, but not for IL-6, revealing a critical role of autocrine secretion of LIF in TNF-α-induced STAT3 activation and astrogliogenesis. This study generates important data elucidating the role of TNF-α in neurogenesis and may provide insight into new therapeutic strategies for brain inflammation.