Interleukin-1β induces a reactive astroglial phenotype via deactivation of the rho GTPase-rock axis
Interleukin-1β induces a reactive astroglial phenotype via deactivation of the rho GTPase-rock axis
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DOI：
10.1523/jneurosci.4789-03.2004
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发表时间：
2004-03-17
影响因子：
5.3
通讯作者：
Brosnan, CF
中科院分区：
文献类型：
--
作者：
John, GR;Chen, LF;Brosnan, CF
细胞因子白细胞介素-1β (IL-1β) 对于中枢神经系统损伤后星形细胞疤痕的形成至关重要，但其诱导反应性表型的机制仍未解决。在这里，我们发现 IL-1beta 通过 Rho GTPase - Rho 激酶 (ROCK) 途径的失活来调节星形胶质细胞的表型，该途径通过影响 F-肌动蛋白及其与粘着斑、非肌肉肌球蛋白和埃兹蛋白 - 根蛋白 - 模蛋白 (ERM) 家族的微绒毛衔接蛋白的相互作用来控制细胞形态和迁移。我们发现，IL-1β 诱导原代人星形胶质细胞中 F-肌动蛋白的皮质重组以及粘着斑激酶、肌球蛋白轻链 2 和肌球蛋白磷酸酶靶向亚基 1 的去磷酸化，并且所有这些效应都可以通过 Rho-ROCK 通路阻断来模拟。我们还发现 IL-1beta 反过来增强 ERM 磷酸化，并且这种作用是通过 Rho - ROCK 独立机制介导的。接下来，我们使用 rhotekin Pulldown 测定直接确认 IL-1beta 使 Rho 失活，并进一步证明组成型活性 Rho 构建体可以挽救星形胶质细胞，使其免于发展 IL-1beta 诱导的反应表型。这些数据表明细胞因子对 Rho - ROCK 通路在反应性星形胶质细胞增多症的产生中的调节，我们建议针对这一水平的干预措施可能有助于控制人类中枢神经系统炎症性疾病中的神经胶质疤痕。
The cytokine interleukin-1beta(IL-1beta) is critical to the formation of an astrocytic scar after CNS injury, but the mechanisms by which it induces a reactive phenotype remain unresolved. Here, we show that IL-1beta regulates the phenotype of astrocytes via deactivation of the Rho GTPase - Rho kinase (ROCK) pathway, which governs cellular morphology and migration via effects on F-actin and its interactions with focal adhesions, nonmuscle myosin, and microvillar adapter proteins of the ezrin - radixin - moesin (ERM) family. We found that IL-1beta induced cortical reorganization of F-actin and dephosphorylation of focal adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1 in primary human astrocytes, and that all of these effects were mimicked by Rho-ROCK pathway blockade. We also found that IL-1beta conversely potentiated ERM phosphorylation, and that this effect was mediated via a Rho - ROCK-independent mechanism. Next, we used a rhotekin pulldown assay to confirm directly that IL-1beta deactivates Rho, and further demonstrated that a constitutively active Rho construct rescued astrocytes from developing an IL-1beta-induced reactive phenotype. These data implicate cytokine regulation of the Rho - ROCK pathway in the generation of a reactive astrogliosis, and we suggest that interventions targeted at this level may facilitate manipulation of the glial scar in inflammatory disorders of the human CNS.