Riva M A, Molteni R, Lovati E, Fumagalli F, Rusnati M, Racagni G
Department of Biological and Technological Research, San Raffaele Hospital, Milan, Italy.
Mol Pharmacol. 1996 Apr;49(4):699-706.
The present study was undertaken to investigate the regulatory mechanisms of fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) gene expression compared with ciliary neurotropic factor (CNTF) in rat cortical astrocytes. Glial cells represent a source of different trophic factors and cytokines that can influence the survival of multiple cell populations within the central nervous system. We found that the beta-adrenergic receptor agonist (betaAR) isoproterenol produced a significant induction of FGF-2 gene expression and protein in type I astrocytes. On the contrary, the gene expression for FGF-1 and CNTF is markedly reduced after exposure to isoproterenol. The changes produced by the beta AR agonist is mimicked by cyclic AMP analogues (8-bromo-cAMP) or 3-isobutyl-1-methyl-xanthine, a cAMP phosphodiesterase inhibitor, which indicates that intracellular elevation of this second messenger is responsible for these effects. The regulation of neurotrophic factors by isoproterenol is not restricted to cortical astrocytes and may take place through different mechanisms. Inhibition of protein synthesis prevents the decrease in CNTF without affecting the changes in FGF-1 and FGF-2 gene expression. Coincubation of isoproterenol with actinomycin D, an inhibitor of gene transcription, prevents the modification of neurotrophic factor biosynthesis, indicating that transcriptional mechanisms are indeed involved in these regulatory pathways. However, the determination of FGF-2 mRNA half-life suggests that the effect of the betaAR agonist can be in part the result of mRNA stabilization. The mechanisms that we describe can be important in the maintenance of neuronal homeostasis and may be relevant in the development of alternative strategies for the treatment of acute and chronic neurodegenerative disorders
本研究旨在探讨与睫状神经营养因子（CNTF）相比，大鼠皮质星形胶质细胞中成纤维细胞生长因子-1和-2（FGF-1和FGF-2）基因表达的调控机制。神经胶质细胞是不同营养因子和细胞因子的来源，这些因子可影响中枢神经系统内多种细胞群的存活。我们发现，β-肾上腺素能受体激动剂（βAR）异丙肾上腺素可显著诱导I型星形胶质细胞中FGF-2基因表达和蛋白质合成。相反，暴露于异丙肾上腺素后，FGF-1和CNTF的基因表达明显降低。βAR激动剂产生的变化可被环磷酸腺苷类似物（8-溴-cAMP）或3-异丁基-1-甲基黄嘌呤（一种cAMP磷酸二酯酶抑制剂）模拟，这表明该第二信使的细胞内升高是造成这些效应的原因。异丙肾上腺素对神经营养因子的调节并不局限于皮质星形胶质细胞，可能通过不同机制发生。蛋白质合成抑制可防止CNTF减少，但不影响FGF-1和FGF-2基因表达的变化。异丙肾上腺素与基因转录抑制剂放线菌素D共同孵育可防止神经营养因子生物合成的改变，表明转录机制确实参与了这些调控途径。然而，FGF-2 mRNA半衰期的测定表明，βAR激动剂的作用部分可能是mRNA稳定的结果。我们所描述的机制可能对维持神经元内环境稳定很重要，并且可能与开发治疗急性和慢性神经退行性疾病的替代策略相关。
