Ma Guozhao, Chen Shengdi, Wang Xijin, Ba Maowen, Yang Hui, Lu Guoqiang
Department of Neurology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China.
J Neurosci Res. 2005 Jun 1;80(5):683-92. doi: 10.1002/jnr.20515.
Several lines of neuroimmunological evidence correlate the development of the inflammatory responses of the brain with the formation of amyloid plaques associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context, we tested the ability of interleukin-1beta (IL-1beta) to regulate the processing of beta-amyloid precursor protein (beta-APP) in neuroglioma U251 cells. Our findings have shown that short-term treatment with IL-1beta (2 hr) resulted in a concentration-dependent decrease in the amount of the cell-associated form of beta-APP in U251 cells as compared to untreated cells, whereas a 2-hr treatment with IL-1beta led to increased release of secreted APP(alpha) fragment (sAPP(alpha)) into the conditioned media of the cells. The fact that sAPP(alpha) is an alpha-secretase cleavage metabolite of the cell-associated form of beta-APP, and the observation that IL-1beta-induced sAPP(alpha) release could be blocked by tissue inhibitors of metalloproteinases-1 (alpha-secretase inhibitors), suggested that alpha-secretase might be involved in IL-1beta-induced-sAPP(alpha) release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1beta-induced increase in sAPP(alpha) secretion, we used various specific signaling inhibitors and found that sAPP(alpha) release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125. These findings suggested that the mechanism of IL-1beta-induced-sAPP(alpha) release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells.
多条神经免疫学证据表明，大脑炎症反应的发展与神经退行性疾病（如阿尔茨海默病）发病机制中相关的淀粉样斑块形成有关。在此背景下，我们测试了白细胞介素-1β（IL-1β）调节神经胶质瘤U251细胞中β-淀粉样前体蛋白（β-APP）加工过程的能力。我们的研究结果表明，与未处理的细胞相比，用IL-1β短期处理（2小时）导致U251细胞中与细胞相关形式的β-APP量呈浓度依赖性降低，而用IL-1β处理2小时导致分泌型APP（α）片段（sAPP（α））释放到细胞条件培养基中增加。sAPP（α）是细胞相关形式的β-APP的α-分泌酶切割代谢产物，并且观察到IL-1β诱导的sAPP（α）释放可被金属蛋白酶-1组织抑制剂（α-分泌酶抑制剂）阻断，这表明α-分泌酶可能参与IL-1β诱导的sAPP（α）释放。此外，为了确定细胞内信号通路是否介导IL-1β诱导的sAPP（α）分泌增加，我们使用了各种特异性信号抑制剂，发现sAPP（α）释放被丝裂原活化蛋白激酶（MEK1/2）抑制剂PD98059和c-Jun N端激酶抑制剂SP600125显著阻断。这些发现表明，IL-1β诱导sAPP（α）释放的机制取决于神经胶质瘤U251细胞中MEK1/2和JNK激活的α-分泌酶切割。
