Differential regulation and function of Fas expression on glial cells
Differential regulation and function of Fas expression on glial cells
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DOI：
10.4049/jimmunol.164.3.1277
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发表时间：
2000-02-01
影响因子：
4.4
通讯作者：
Benveniste, EN
中科院分区：
文献类型：
--
作者：
Lee, SJ;Zhou, T;Benveniste, EN
Fas/Apo-1是TNF受体超家族的成员，在易感靶细胞中发出凋亡细胞死亡的信号。Fas或Fas配体（FasL）缺陷小鼠对实验性变态反应性脑脊髓炎的诱导具有相对抗性，这意味着Fas/FasL参与了该疾病过程。我们研究了Fas在神经胶质细胞（星形胶质细胞和小胶质细胞）中的表达的调节和功能，Fas在原代小鼠小胶质细胞中以低水平组成性表达，并且在TNF-α或IFN-γ刺激下显著上调。原代星形胶质细胞表达高组成性水平的Fas，其不受细胞因子处理的进一步影响。在小胶质细胞中，Fas表达在mRNA表达水平上受到调节; TNF-α和IFN-γ诱导Fas mRNA的表达，其诱导倍数接近20倍。STAT-1 α和NF-κ B活化分别参与小胶质细胞中IFN-γ或TNF-α介导的Fas上调。细胞因子TGF-β抑制Fas的基础表达以及小胶质细胞介导的Fas表达。在将小胶质细胞与表达Fas的细胞孵育后，约20%的细胞经历Fas介导的细胞死亡，当用TNF-α或IFN-γ预处理细胞时，其增加至约60%。TGF-β处理抑制Fas介导的TNF-α或IFN-γ刺激的小胶质细胞的细胞死亡。相比之下，星形胶质细胞对Fas介导的细胞死亡具有抗性，然而，Fas的连接诱导趋化因子巨噬细胞炎性蛋白-1 β（MIP-1 β）、MIP-1 α和MIP-2的表达。这些数据表明，Fas在两个神经胶质细胞群体中传递不同的信号：小胶质细胞中的细胞毒性信号和星形胶质细胞中的炎症信号。
Fas/Apo-1 is a member of the TNF receptor superfamily that signals apoptotic cell death in susceptible target cells. Fas or Fas ligand (FasL)-deficient mice are relatively resistant to the induction of experimental allergic encephalomyelitis, implying the involvement of Fas/FasL in this disease process. We have examined the regulation and function of Fas expression in glial cells (astrocytes and microglia), Fas is constitutively expressed by primary murine microglia at a low level and significantly upregulated by TNF-alpha or IFN-gamma stimulation. Primary astrocytes express high constitutive levels of Fas, which are not further affected by cytokine treatment. In microglia, Fas expression is regulated at the level of mRNA expression; TNF-alpha and IFN-gamma induced Fas mRNA by similar to 20-fold. STAT-1 alpha and NF-kappa B activation are involved in IFN-gamma- or TNF-alpha-mediated Fas up-regulation in microglia, respectively. The cytokine TGF-beta inhibits basal expression of Fas as well as cytokine-mediated Fas expression by microglia, Upon incubation of microglial cells with Fast-expressing cells, similar to 20% of cells underwent Fas-mediated cell death, which increased to similar to 60% when cells were pretreated with either TNF-alpha or IFN-gamma, TGF-beta treatment inhibited Fas-mediated cell death of TNF-alpha- or IFN-gamma-stimulated microglial cells. In contrast, astrocytes are resistant to Fas-mediated cell death, however, ligation of Fas induces expression of the chemokines macrophage inflammatory protein-1 beta (MIP-1 beta), MIP-1 alpha, and MIP-2. These data demonstrate that Fas transmits different signals in the two glial cell populations: a cytotoxic signal in microglia and an inflammatory signal in the astrocyte.