Astrocyte protection of neurons -: Role of transforming growth factor-β signaling via a c-Jun-AP-1 protective pathway
Astrocyte protection of neurons -: Role of transforming growth factor-β signaling via a c-Jun-AP-1 protective pathway
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DOI：
10.1074/jbc.m305835200
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发表时间：
2003-10-31
影响因子：
4.8
通讯作者：
Brann, DW
中科院分区：
文献类型：
--
作者：
Dhandapani, KM;Hadman, M;Brann, DW
星形胶质细胞已成为神经生物学研究的焦点，特别是关于它们调节神经元通讯和存活的能力。目前的研究解决了这一领域一个鲜为人知但重要的焦点，即星形胶质细胞诱导神经元存活的机制。研究结果表明，星形胶质细胞条件介质（ACM）中的可溶性因子保护小鼠GT1-7神经元免受血清剥夺诱导的细胞死亡，这种神经保护与AP-1转录因子c-Jun（Ser-63）的激活/磷酸化增强有关。上游激酶，c-Jun n-末端激酶（JNK）和丝裂原活化蛋白激酶激酶-4 （MKK4）的平行和相关激活也被证实。此外，联合使用JNK抑制剂，而不是MEK抑制剂，可显著减弱acm诱导的c-Jun（Ser-63）磷酸化，并阻断其神经保护作用。凝胶位移分析表明，ACM增强了AP-1的结合，这一作用在功能上似乎很重要，因为AP-1结合抑制剂显著减弱了ACM的神经保护作用。进一步的研究表明，转化生长因子(TGF)- β 1和TGF- β 2是星形胶质细胞释放的关键活性可溶性因子，因为这两种因子都在ACM中得到证实，并且用泛特异性TGF- β抗体免疫中和条件培养基显著减弱了ACM增强的AP-1结合和神经保护作用。此外，外源性应用tgf - β 1和tgf - β 2被发现增强c-Jun（Ser-63）磷酸化并具有神经保护作用，同时使用JNK抑制剂或AP-1结合抑制剂可阻断tgf - β诱导的神经保护作用。综上所述，这些研究表明星形胶质细胞可以保护神经元免受血清剥夺诱导的细胞死亡，至少部分是通过释放tgf - β和激活c-Jun/AP-1保护通路。
Astrocytes have become a focal point for research in neurobiology, especially regarding their purported ability to regulate neuronal communication and survival. The present study addressed a poorly understood but important focus in this area, the mechanism(s) underlying astrocyte-induced survival of neurons. The results of the study show that soluble factors in astrocyte-conditioned media (ACM) protect murine GT1-7 neurons from serum deprivation-induced cell death and that this neuroprotection is correlated with enhanced activation/phosphorylation of the AP-1 transcription factor, c-Jun(Ser-63). A parallel and correlated activation of the upstream kinases, c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase-4 (MKK4) was also demonstrated. Furthermore, co-administration of JNK inhibitors, but not a MEK inhibitor, significantly attenuated ACM-induced phosphorylation of c-Jun(Ser-63) and blocked its neuroprotective action. Gel shift analysis demonstrated that ACM enhanced AP-1 binding, an effect that appears functionally important, since an AP-1 binding inhibitor significantly attenuated the neuroprotective action of ACM. Further studies implicated transforming growth factor (TGF)-beta1 and TGF-beta2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-beta antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-beta1 and TGF-beta2 was found to enhance c-Jun(Ser-63) phosphorylation and to be neuroprotective, and co-administration of JNK inhibitors or an AP-1 binding inhibitor blocked TGF-beta-induced neuroprotection. Taken together, these studies suggest that astrocytes can protect neurons from serum deprivation-induced cell death, at least in part, by release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.