Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia
Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia
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DOI：
10.4049/jimmunol.171.11.5802
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Suk, K
中科院分区：
文献类型：
--
作者：
Lee, H;Cha, S;Suk, K
小鼠脑小胶质细胞在暴露于炎症刺激时发生凋亡，这被认为是控制其自身激活的自动调节机制。在这里，我们提出的证据表明，抗增殖B细胞易位基因1（BTG 1）构成了一种新的LPS/IFN-γ激活的小胶质细胞凋亡途径。在BV-2小鼠小胶质细胞以及原代小胶质细胞培养物中，LPS和IFN-γ协同增强BTG 1的表达。BTG 1表达水平与小胶质细胞的增殖能力呈负相关。基于四环素的BTG 1的条件性表达不仅抑制小胶质细胞增殖，而且还增加了小胶质细胞对NO诱导的凋亡的敏感性，这表明LPS和IFN-γ在诱导小胶质细胞凋亡中的新的合作机制。然而，BTG 1表达的增加并不影响小胶质细胞NO、TNF-α或IL-1 β的产生，这表明抗增殖BTG 1在小胶质细胞活化诱导的凋亡中很重要，但在活化本身中不重要。LPS和IFN-γ在小胶质细胞BTG 1诱导和凋亡中的协同作用依赖于Janus激酶/STAT 1途径，而不是IFN-调节因子-1，如Janus激酶（AG 490）的药理学抑制剂、STAT 1显性负突变体和IFN-调节因子-1缺陷小鼠所示。两者合计，抗增殖BTG 1可能参与激活诱导的细胞死亡的小胶质细胞通过降低凋亡的阈值; BTG 1增加了小胶质细胞的自分泌细胞毒性介质，NO的致瘤作用的敏感性。我们的研究结果指出了小胶质细胞的增殖状态和它们对致瘤剂的敏感性之间的重要联系。
Mouse brain microglial cells undergo apoptosis on exposure to inflammatory stimuli, which is considered as an autoregulatory mechanism to control their own activation. Here, we present evidence that an antiproliferative B cell translocation gene 1 (BTG1) constitutes a novel apoptotic pathway of LPS/IFN-gamma-activated microglia. The expression of BTG1 was synergistically enhanced by LPS and IFN-gamma in BV-2 mouse microglial cells as well as in primary microglia cultures. Levels of BTG1 expression inversely correlated with a proliferative capacity of the microglial cells. Tetracycline-based conditional expression of BTG1 not only suppressed microglial proliferation but also increased the sensitivity of microglial cells to NO-induced apoptosis, suggesting a novel mechanism of cooperation, between LPS and IFN-gamma in the induction of microglial apoptosis. An increase in BTG1 expression, however, did not affect microglial production of NO, TNF-alpha, or IL-1beta, indicating that the antiproliferative BTG1 is important in the activation-induced apoptosis of microglia, but not in the activation itself. The synergistic action of LPS and IFN-gamma in the microglial BTG1 induction and apoptosis was dependent on the Janus kinase/STAT1 pathway, but not IFN-regulatory factor-1, as demonstrated by a pharmacological inhibitor of Janus kinase (AG490), STAT1 dominant negative mutant, and IFN-regulatory factor-1-deficient mice. Taken together, antiproliferative BTG1 may participate in the activation-induced cell death of microglia by lowering the threshold for apoptosis; BTG1 increases the sensitivity of microglia to apoptogenic action of autocrine cytotoxic mediator, NO. Our results point out an important link between the proliferative state of microglia and their sensitivity to apoptogenic agents.