F-spondin plays a critical role in murine neuroblastoma survival by maintaining IL-6 expression
F-spondin plays a critical role in murine neuroblastoma survival by maintaining IL-6 expression
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DOI：
10.1111/j.1471-4159.2009.06186.x
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发表时间：
2009-08-01
影响因子：
4.7
通讯作者：
Liang, Shu-Mei
中科院分区：
文献类型：
--
作者：
Cheng, Yung-Chih;Liang, Chi-Ming;Liang, Shu-Mei
F-响应蛋白与轴突生长和神经系统发育的调节有关。然而，其作用机制尚不清楚。在本研究中，我们发现小鼠神经母细胞瘤Neuro-2a细胞表达显著水平的IL-6，但仅有微量的IL-12、肿瘤坏死因子α和一氧化氮。用小干扰RNA敲除小鼠神经母细胞瘤NB41A3和Neuro-2a细胞中的F-pondin mRNA，导致IL-6水平降低，并降低了对血清饥饿和细胞毒性淀粉样β(1-42)(Aβ(1-42))肽的抵抗力。通过加入外源性F响应素、IL-6或过表达的F响应素来恢复由F响应素基因敲除引起的F响应素或IL-6的下降，可逆转Aβ(1-42)肽或血清饥饿所致的细胞死亡。IL-6水平的降低与核因子-kappaB的降低和p38丝裂原活化蛋白激酶(MAPK)的抑制呈正相关。P38MAPK通路激活剂Mekk的过表达增加了IL-6的产生，恢复了F-pondin基因敲除引起的p38表达的下降，并使Aβ(1-42)多肽引起的细胞免于死亡。综上所述，这些结果提示，通过依赖于Mekk/p38MAPK/NF-kappa B的途径维持IL-6水平，F-pondin可能在恶劣条件下小鼠神经母细胞瘤的存活中发挥关键作用。
F-spondin is associated with the regulation of axonal growth and the development of the nervous system. Its mechanism of action, however, is not clearly understood. In this study, we found that murine neuroblastoma Neuro-2a cells expressed a significant level of IL-6, but only trace amounts of IL-12, tumor necrosis factor alpha and nitric oxide. Knock-down of F-spondin mRNA in murine neuroblastoma NB41A3 and Neuro-2a cells using small interfering RNAs led to decreased IL-6 levels along with lower resistance to serum starvation and cytotoxic amyloid beta(1-42) (A beta(1-42)) peptide. Restoring decline of F-spondin or IL-6 induced by F-spondin knock-down through adding exogenous F-spondin, IL-6 or over-expressing F-spondin reversed the cell death induced by A beta(1-42) peptide or serum starvation. The decrease of IL-6 level was positively correlated with decrease of NF-kappa B and inhibition of p38 mitogen-activated protein kinase (MAPK). Over-expressing MEKK, a kinase activator of the p38 MAPK pathway, increased IL-6 production, restored the decrease of p38 induced by F-spondin knock-down, and rescued the cells from death caused by A beta(1-42) peptide. Taken together, these results suggest that F-spondin may play a critical role in murine neuroblastoma survival under adverse conditions by maintaining IL-6 level via a MEKK/p38 MAPK/NF-kappa B-dependent pathway.