Lee Heasuk, Cha Sanghoon, Lee Myung-Shik, Cho Gyeong Jae, Choi Wan Sung, Suk Kyoungho
Department of Anatomy and Neurobiology and Research Institute of Natural Science, Gyeongsang National University College of Medicine, Institute of Health Sciences, Jinju, Korea.
J Immunol. 2003 Dec 1;171(11):5802-11. doi: 10.4049/jimmunol.171.11.5802.
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.
小鼠脑小胶质细胞在受到炎症刺激时会发生凋亡，这被认为是一种控制自身激活的自动调节机制。在此，我们提供证据表明，抗增殖的B细胞易位基因1（BTG1）构成了脂多糖/γ干扰素激活的小胶质细胞的一条新的凋亡途径。在BV-2小鼠小胶质细胞以及原代小胶质细胞培养物中，脂多糖和γ干扰素协同增强了BTG1的表达。BTG1的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BTG1条件性表达不仅抑制了小胶质细胞的增殖，还增加了小胶质细胞对一氧化氮诱导的凋亡的敏感性，提示脂多糖和γ干扰素在诱导小胶质细胞凋亡过程中存在一种新的协同机制。然而，BTG1表达的增加并不影响小胶质细胞一氧化氮、肿瘤坏死因子-α或白细胞介素-1β的产生，这表明抗增殖的BTG1在激活诱导的小胶质细胞凋亡中很重要，但在激活本身中并不重要。脂多糖和γ干扰素在小胶质细胞BTG1诱导及凋亡中的协同作用依赖于Janus激酶/信号转导和转录激活因子1（STAT1）途径，而非干扰素调节因子-1，这是通过Janus激酶的药理学抑制剂（AG490）、STAT1显性负性突变体以及干扰素调节因子-1缺陷小鼠所证实的。综上所述，抗增殖的BTG1可能通过降低凋亡阈值参与激活诱导的小胶质细胞死亡；BTG1增加了小胶质细胞对自分泌细胞毒性介质一氧化氮的凋亡作用的敏感性。我们的结果指出了小胶质细胞的增殖状态与其对凋亡因子敏感性之间的重要联系。
