Thrombin-induced regulation of CD95(Fas) expression in the N9 microglial cell line: evidence for involvement of proteinase-activated receptor(1) and extracellular signal-regulated kinase 1/2.
Thrombin-induced regulation of CD95(Fas) expression in the N9 microglial cell line: evidence for involvement of proteinase-activated receptor(1) and extracellular signal-regulated kinase 1/2.
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N9 小胶质细胞系中凝血酶诱导的 CD95(Fas) 表达调节：蛋白酶激活受体 (1) 和细胞外信号调节激酶 1/2 参与的证据。
DOI：
10.1007/s11064-008-9803-9
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发表时间：
2009
影响因子：
4.4
通讯作者：
Möller,Thomas
中科院分区：
文献类型：
--
作者：
Weinstein,JonathanR;Zhang,Matthew;Kutlubaev,Mansur;Lee,Richard;Bishop,Caroline;Andersen,Henrik;Hanisch,Uwe-Karsten;Möller,Thomas
小胶质细胞是中枢神经系统的免疫细胞。脑损伤触发小胶质细胞的表型变化，包括表面抗原的调节。丝氨酸蛋白酶α-凝血酶可通过切割蛋白酶激活受体（PARs）而引起神经细胞生理学的深刻变化。我们最近证明，药用级重组人α-凝血酶（rh-thr）诱导小胶质细胞的蛋白水解依赖性变化的限制集。CD 95（Fas）是一种细胞死亡受体，在小胶质细胞中受到炎症刺激而上调。在这里，我们的特点的影响，rh-thr对CD 95（Fas）的表达在N9小胶质细胞系。剂量反应和时间过程研究表明，最大效应分别在100 U/ml和24小时。在表面蛋白和稳态mRNA水平上均观察到表达调节。rh-thr诱导的效应被PAR 1激动剂肽模拟，并被细胞外信号调节激酶1/2（ERK 1/2）选择性药理学抑制剂阻断。Rh-thr还诱导ERK 1/2的快速和持续的磷酸化。凝血酶诱导的CD 95（Fas）调节可以调节多种神经系统疾病的神经炎症反应。
Microglia are the immune cells of the CNS. Brain injury triggers phenotypic changes in microglia including regulation of surface antigens. The serine proteinase α-thrombin can induce profound changes in neural cell physiology via cleavage of proteinase-activated receptors (PARs). We recently demonstrated that pharmaceutical-grade recombinant human α-thrombin (rh-thr) induces a restricted set of proteolysis-dependent changes in microglia. CD95(Fas) is a cell-death receptor that is up-regulated in microglia by inflammatory stimuli. Here we characterized the effect of rh-thr on CD95(Fas) expression in the N9 microglial cell line. Dose–response and time course studies demonstrated maximal effects at 100 U/ml and 24 h, respectively. Regulation of expression was seen at both the surface protein and steady-state mRNA levels. The rh-thr-induced effects were mimicked by PAR1agonist peptides and blocked by pharmacologic inhibitors selective for extracellular signal-regulated kinase 1/2 (ERK 1/2). Rh-thr also induced a rapid and sustained phosphorylation of ERK 1/2. Thrombin-induced regulation of CD95(Fas) could modulate the neuroinflammatory response in a variety of neurological disorders.