Department of Life Science and Biotechnology, University of Ferrara, via L. Bersari, 46, 44121 Ferrara, Italy.
Neuroscience. 2013 Nov 12;252:367-83. doi: 10.1016/j.neuroscience.2013.07.061. Epub 2013 Aug 6.
Reactive astrogliosis, a feature of neuro-inflammation is induced by a number of endogenous mediators including cytokines. Despite interleukin-1 beta (IL-1β) stands out as the major inducer of this process, the underlying mechanism and its role on neuronal viability remain elusive. We investigated in human astrocytoma cells and the rat brain striatum, the role of the nuclear factor-kB (NF-kB) intracellular Ca(2+) concentration ([Ca(2+)]i) calmodulin (CaM) and extracellular regulated mitogen-activated protein kinases (ERK1/2) in IL-1β-induced expression of glial fibrillary acidic protein (GFAP) and neuronal apoptosis associated to a brain trauma. Cell data showed that IL-1β (1 ng/ml) increased NF-kB, pERK1/2 and GFAP expression. Nevertheless, further increase in IL-1β levels reversed progressively these responses. Preventing ERK1/2 activation with 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthiol]-butadiene antagonized IL-1β-induced GFAP expression while inhibiting selectively nuclear translocation of NF-kB with caffeic-acid phenethyl-ester down-regulated both ERK1/2 and GFAP expression induced by IL-1β. The GFAP response was also prevented by antagonizing selectively increase in [Ca(2+)]i, CaM activity or inducible nitric oxide synthase expression with respectively ryanodine plus 2-aminoethoxydiphenyl-borate, N-(6-aminohexyl)-5-chloro-1-naphthalensulfonamide hydrochloride and N-[(3-(aminomethyl)-phenyl]methyl]-ethanimidamide dihydrochloride. Data in vivo supported these findings and showed that GFAP expression induced by IL-1β (50 ng/ml) correlated with attenuated glial scar formation and reduced neuronal apoptosis. Our data identified the NF-kB/Ca(2+)-CaM/ERK signaling pathway as a novel in vivo key regulator of IL-1β-induced astrogliosis which may represent a potential target in neurodegeneration.
反应性星形胶质细胞增生是神经炎症的一个特征，由许多内源性介质引起，包括细胞因子。尽管白细胞介素-1β（IL-1β）是诱导该过程的主要介质，但潜在的机制及其对神经元活力的作用仍不清楚。我们在人星形胶质细胞瘤细胞和大鼠纹状体中研究了核因子-kB（NF-kB）细胞内 Ca2+浓度([Ca2+]i)钙调蛋白（CaM）和细胞外调节的丝裂原激活蛋白激酶（ERK1/2）在 IL-1β诱导的神经胶质纤维酸性蛋白（GFAP）表达和与脑外伤相关的神经元凋亡中的作用。细胞数据显示，IL-1β（1ng/ml）增加了 NF-kB、pERK1/2 和 GFAP 的表达。然而，IL-1β 水平的进一步增加逐渐逆转了这些反应。用 1,4-二氨基-2,3-二氰基-1,4-双[2-氨基苯基硫代]-丁二烯阻断 ERK1/2 的激活，拮抗了 IL-1β 诱导的 GFAP 表达，而用咖啡酸苯乙酯选择性抑制 NF-kB 的核易位则下调了 IL-1β 诱导的 ERK1/2 和 GFAP 的表达。通过分别用 Ryanodine 加 2-氨基乙氧基二苯硼酸、N-（6-氨基己基）-5-氯-1-萘磺酰胺盐酸盐和 N-[(3-（氨甲基）-苯基）甲基]-乙亚胺二盐酸盐选择性拮抗[Ca2+]i、CaM 活性或诱导型一氧化氮合酶表达，也阻止了 GFAP 反应。体内数据支持了这些发现，并表明 IL-1β（50ng/ml）诱导的 GFAP 表达与减弱的神经胶质瘢痕形成和减少的神经元凋亡相关。我们的数据确定了 NF-kB/Ca2+-CaM/ERK 信号通路作为 IL-1β 诱导的星形胶质细胞增生的一种新的体内关键调节因子，它可能是神经退行性变的一个潜在靶点。
