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中枢神经系统(CNS)慢性炎性反应是许多神经退行性疾病和自身免疫性疾病的主要病理特点之一。作为免疫活性细胞,星形胶质细胞(Ast)在CNS炎性反应过程中发挥了重要作用。它可表达许多细胞因子,如肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)等,这些细胞因子可直接或通过募集免疫细胞等途径间接促进炎性反应。检测点的存在可保证这些细胞因子的生成受到严密控制。细胞因子mRNA3’-非翻译区的腺苷酸/尿苷酸富含元件(ARE)由于可调节mRNA稳定性和翻译效率而扮演着主要检测点的角色。KH型剪切调控蛋白(KSRP)是一种RNA结合蛋白,可通过与ARE结合降低mRNA的稳定性。本研究检测了KSRP对Ast细胞因子表达和旁分泌表型的影响。笔者发现了一个包括TNF-α和L-1β在内的炎性介质网络。与同窝出生的对照小鼠相比,KSRP-/-小鼠Ast上述炎性介质的表达在RNA水平增高了2～4倍。而这种KSRP-/-小鼠Ast激活后产生的TNF-α和IL-1β甚至能达到对照组的15倍以上。离体情况下,KSRP-/-Ast条件性培养液有趋化作用且能诱导神经元死亡。令人惊讶的是,笔者发现仅通过特定途径激活Ast后才能观察到部分mRNA半衰期延长。荧光素酶报告系统研究显示KSRP可在转录水平和转录后水平调节细胞因子基因的表达。本研究提示KSRP在促炎介质的调控方面发挥重要作用,因此在CNS炎性和自身免疫性疾病中有广泛意义。
Central nervous system (CNS) Chronic inflammatory response is one of the major pathological features of many neurodegenerative and autoimmune diseases. As an immunocompetent cell, astrocytes (Ast) play an important role in the inflammatory reaction of CNS. It expresses many cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). These cytokines can indirectly promote inflammatory reaction directly or through recruitment of immune cells and other pathways. The presence of test sites ensures that the production of these cytokines is tightly controlled. The adenylate / uridylate-rich elements (AREs) of the cytokine mRNA3’-untranslated region play a major role as checkpoints due to the regulation of mRNA stability and translation efficiency. KH-type shear regulatory protein (KSRP) is an RNA-binding protein that reduces mRNA stability by binding to ARE. This study examined the effects of KSRP on Ast cytokine expression and paracrine phenotypes. I found a network of inflammatory mediators, including TNF-α and L-1β. Compared with littermate control mice, the expression of above inflammatory mediators of KSRP - / - mouse Ast had two to four times higher levels of RNA at RNA level. The TNF-α and IL-1β produced by this KSRP - / - mice after activation of AstR were even more than 15 times of the control group. In vitro, KSRP - / - Ast conditioned medium has chemotactic effects and can induce neuronal death. Surprisingly, I found that partial mRNA half-life extension was observed only after activation of Ast by a specific pathway. Luciferase reporter system studies have shown that KSRP regulates the expression of cytokine genes at the transcription and post-transcriptional levels. This study suggests that KSRP plays an important role in the regulation of proinflammatory mediators and therefore has a wide range of implications in CNS inflammatory and autoimmune diseases.