The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia
The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia
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DOI：
10.4049/jimmunol.165.1.397
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发表时间：
2000-07-01
影响因子：
4.4
通讯作者：
Conlon, PJ
中科院分区：
文献类型：
--
作者：
Boehme, SA;Lio, FM;Conlon, PJ
Fractalkine是一种CX3C家族趋化因子，在神经细胞表面高表达，其中枢神经系统的生理功能尚不明确。它的同源受体CX3CR-1在脑内的巨噬细胞小胶质细胞上有结构性表达，但这些细胞不表达Fractalkine。我们的研究表明，在体外，Fractalkine处理小胶质细胞可以维持细胞存活，并抑制Fas配体诱导的细胞死亡。生化特征表明，BAD的发生机制可能包括：1)激活磷脂酰肌醇-3激酶/蛋白激酶B通路，导致BAD的促凋亡功能被磷酸化和阻断，2)抗凋亡蛋白Bclx上调(L)；3)抑制BH3相互作用域死亡激动剂(BID)的切割，观察到Fractalkine部分通过调节蛋白水平和Bcl2家族蛋白的磷酸化状态作为原代小胶质细胞的生存因子，揭示了趋化因子的一个新的生理作用，因此，这些结果提示，Fractalkine与CX3CR-1的相互作用可能在促进和维持中枢小胶质细胞存活方面发挥重要作用。
Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine, We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-x(L); and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID), The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines, These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.