TNF-α Affects Human Cortical Neural Progenitor Cell Differentiation through the Autocrine Secretion of Leukemia Inhibitory Factor

被引：29
作者：
Lan, Xiqian [1 ,2 ]
Chen, Qiang [1 ,2 ]
Wang, Yongxiang [1 ,2 ]
Jia, Beibei [1 ,2 ]
Sun, Lijun [1 ,2 ]
Zheng, Jialin [1 ,2 ,3 ]
Peng, Hui [1 ,2 ]
机构：
[1] Univ Nebraska Med Ctr, Lab Neuroimmunol & Regenerat Therapy, Omaha, NE 68198 USA
[2] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE USA
[3] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA
来源：
PLOS ONE | 2012年 / 7卷 / 12期
基金：
美国国家卫生研究院;
关键词：
CENTRAL-NERVOUS-SYSTEM; ADULT MAMMALIAN BRAIN; NECROSIS-FACTOR-ALPHA; STEM-CELLS; PRECURSOR CELLS; ASTROCYTIC DIFFERENTIATION; SUBVENTRICULAR ZONE; IN-VITRO; NEUROGENESIS; MICROGLIA;
D O I：
10.1371/journal.pone.0050783
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) 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-alpha negatively regulates embryonic and adult neurogenesis. However, the effect of TNF-alpha on cell fate decision in human neural progenitor cells (NPCs) has rarely been studied. Our previous studies have shown that recombinant TNF-alpha 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-alpha-induced astrogliogenesis. We found that TNF-alpha activated STAT3 at delayed time points (6 h and 24 h), whereas conditioned medium collected from TNF-alpha-treated NPCs induced an immediate STAT3 activation. These data suggest TNF-alpha plays an indirect role on STAT3 activation and the subsequent NPC differentiation. Further, we showed that TNF-alpha induced abundant amounts of the IL-6 family cytokines, including Leukemia inhibitory factor (LIF) and Interleukin 6 (IL-6), in human NPCs. TNF-alpha-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-alpha-induced STAT3 activation and astrogliogenesis. This study generates important data elucidating the role of TNF-alpha in neurogenesis and may provide insight into new therapeutic strategies for brain inflammation.
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页数：8
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