Limitation by Rho-kinase and Rac of transforming growth factor-β-induced interleukin-6 release from astrocytes
Limitation by Rho-kinase and Rac of transforming growth factor-β-induced interleukin-6 release from astrocytes
复制标题
Rho-激酶和 Rac 对转化生长因子-β 诱导的星形胶质细胞释放白细胞介素 6 的限制
DOI：
10.1016/j.neulet.2018.12.040
复制
发表时间：
2019
影响因子：
2.5
通讯作者：
Iida Hiroki
中科院分区：
文献类型：
--
作者：
Tanabe Kumiko;Kojima Akiko;Tachi Junko;Nakashima Daiki;Kozawa Osamu;Iida Hiroki
转化生长因子 (TGF)-β 刺激星形胶质细胞释放白细胞介素 (IL)-6，白介素 (IL)-6 被认为在中枢神经系统中具有促炎和抗炎细胞因子的作用。人们普遍认为，TGF-β 的作用是通过 Smad 独立途径和 Smad 依赖性途径介导的。小 GTP 酶调节多种细胞功能。在本研究中，我们研究了 Rho 激酶（Rho 的下游效应子）和 Rac 是否与星形胶质细胞（C8D1A 细胞）中 TGF-β 刺激的 IL-6 释放有关。 Y-27632 或 fasudil（Rho 激酶抑制剂）或 NSC23766（Rac-鸟嘌呤核苷酸交换因子相互作用的抑制剂）显着增强这些细胞中 TGF-β 刺激的 IL-6 释放。在 RhoA 或 Rac 敲低的 C8D1A 细胞中，TGF-β 刺激的 IL-6 释放显着上调。我们发现SIS3（TGF-β依赖性Smad3磷酸化的特异性抑制剂）或LY364947（TGF-β I型受体激酶抑制剂）显着减少IL-6的释放。然而，TGF-β诱导的 Smad2 和 Smad3 磷酸化不受 Y-27632、法舒地尔或 NSC23766 的影响。总之，我们的结果强烈表明，Rho 激酶和 Rac 限制 TGF-β 诱导的星形胶质细胞释放 IL-6，并且抑制作用的发挥独立于 Smad 途径或在 Smad2/3 复合物的下游点。
Transforming growth factor (TGF)-β stimulates release of interleukin (IL)-6, which is recognized to function as both a pro- and anti- inflammatory cytokine in the central nervous system, from astrocytes. It is generally recognized that effects of TGF-β are mediated through Smad-independent as well as Smad-dependent pathways. Small GTPases regulate a variety of cell functions. In the present study, we investigated whether or not Rho-kinase, a downstream effector of Rho, and Rac are implicated in TGF-β-stimulated IL-6 release from astrocytes (C8D1A cells). Y-27632 or fasudil (Rho-kinase inhibitors) or NSC23766 (an inhibitor of Rac-guanine nucleotide exchange factor interaction) significantly enhanced TGF-β-stimulated IL-6 release from these cells. TGF-β-stimulated IL-6 release was markedly upregulated in RhoA- or Rac-knockdown C8D1A cells. We found that SIS3 (a specific inhibitor of TGF-β-dependent Smad3 phosphorylation) or LY364947 (a TGF-β type I receptor kinase inhibitor) significantly reduced the IL-6 release. However, TGF-β-induced-Smad2 and Smad3 phosphorylation was not affected by Y-27632, fasudil or NSC23766. In conclusion, our results strongly suggest that Rho-kinase and Rac limit TGF-β-induced IL-6 release from astrocytes, and the suppressive effects are exerted independently of the Smad pathway or at a point downstream of Smad2/3 complex.