Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase.
Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase.
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
Chulhee Choi;Xiang Xu;Jae Wook Oh;Sung Joong Lee;G. Gillespie;Heonyong Park;Hanjoong Jo;Etty N. Benveniste
中科院分区：
文献类型：
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作者：
Chulhee Choi;Xiang Xu;Jae Wook Oh;Sung Joong Lee;G. Gillespie;Heonyong Park;Hanjoong Jo;Etty N. Benveniste
Fas不仅通过多种途径传递凋亡信号，而且还参与体内血管生成和促炎反应。人神经胶质瘤细胞表达Fas，但Fas介导的细胞死亡的敏感性是可变的，这表明Fas可能有功能以外的凋亡，在这些细胞。在这项研究中，我们解决了替代功能的Fas表达的人脑胶质瘤细胞系，CRT-MG，U373-MG，和U87-MG，在人类胶质母细胞瘤（GBM）的Fas连接，并在体内表达的Fas和趋化因子。在此，我们证明：（a）用激动性抗Fas单克隆抗体CH-11和人重组可溶性Fas配体刺激，以剂量和时间依赖性方式诱导人神经胶质瘤细胞系在mRNA和蛋白质水平表达CC趋化因子MCP-1和CXC趋化因子白细胞介素-8;（B）MEK 1的选择性药理学抑制剂（U 0126和PD 98059）和p38丝裂原活化蛋白激酶（MAPK）（c）人神经胶质瘤细胞上的Fas连接导致细胞外信号调节激酶ERK 1/ERK 2和p38 MAPK的激活;和（d）与正常对照脑相比，GBM样品表达更高水平的Fas，这与增加的白细胞介素8表达相关。这些结果表明，Fas在人脑胶质瘤细胞上的连接导致选择性诱导趋化因子的表达，这涉及ERK 1/ERK 2和p38 MAPK信号通路。因此，Fas-Fas配体系统在人脑肿瘤中可能不仅参与凋亡过程，而且还参与血管生成和促炎反应的激发。
Fas transduces not only apoptotic signals through various pathways but also angiogenic and proinflammatory responses in vivo. Human glioma cells express Fas although sensitivity to Fas-mediated cell death is variable, suggesting that Fas may have functions other than apoptosis in these cells. In this study, we addressed alternative functions of Fas expressed on human gliomas by Fas ligation in three human glioma cell lines, CRT-MG, U373-MG, and U87-MG, and the in vivo expression of Fas and chemokines in human glioblastoma multiforme (GBM). Herein, we demonstrate that: (a) stimulation with agonistic anti-Fas monoclonal antibody CH-11 and human recombinant soluble Fas ligand induces expression of the CC chemokine MCP-1 and the CXC chemokine interleukin-8 by human glioma cell lines at the mRNA and protein levels in a dose- and time-dependent manner; (b) selective pharmacological inhibitors of MEK1 (U0126 and PD98059) and p38 mitogen-activated protein kinase (MAPK) (SB202190) suppress Fas-mediated chemokine expression in a dose-dependent manner; (c) Fas ligation on human glioma cells leads to activation of both extracellular signal-regulated kinases ERK1/ERK2 and p38 MAPK; and (d) GBM samples express higher levels of Fas compared with normal control brain, which correlates with increased interleukin 8 expression. These findings indicate that Fas ligation on human glioma cells leads to the selective induction of chemokine expression, which involves the ERK1/ERK2 and p38 MAPK signaling pathways. Therefore, the Fas-Fas ligand system in human brain tumors may be involved not only in apoptotic processes but also in the provocation of angiogenic and proinflammatory responses.