IL-1β potently stabilizes IL-6 mRNA in human astrocytes
IL-1β potently stabilizes IL-6 mRNA in human astrocytes
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DOI：
10.1016/j.bcp.2011.01.019
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发表时间：
2011-04-15
影响因子：
5.8
通讯作者：
Gerlo, Sarah
中科院分区：
文献类型：
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作者：
Spooren, Anneleen;Mestdagh, Pieter;Gerlo, Sarah
中枢神经系统中IL-6的不受控制的表达与神经退行性病变和胶质瘤的发展有关。星形胶质细胞是中枢神经系统中IL-6的主要来源，它们对IL-6的协同表达具有明显的易感性。联合使用β-肾上腺素能和肿瘤坏死因子受体可通过转录增强机制诱导1321N1细胞协同表达IL-6。在这里，我们研究了星形胶质细胞与β-肾上腺素能激动剂异丙肾上腺素和炎性细胞因子TNF-α和IL-1β联合处理后，非常有效的超协同IL-6表达的分子基础。我们发现，IL-1β治疗通过诱导IL-6mRNA的明显稳定来增强IL-6的协同作用。令人惊讶的是，稳定信使核糖核酸的作用似乎依赖于蛋白激酶C(PKC)，而不是依赖于典型的信使核糖核酸稳定激酶p38。此外，尽管信使核糖核酸结合蛋白HUR基本稳定IL-6的信使核糖核酸，但IL-1β的信使核糖核酸的稳定作用不依赖于HUR。我们使用药物抑制剂的数据表明，PKC是中枢神经系统IL-6表达的重要调节器，这可能具有治疗意义。(C)2011 Elsevier Inc.保留所有权利。
Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined beta-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a beta-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-alpha and IL-1 beta. We found that IL-1 beta treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNA-stabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1 beta is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications. (C) 2011 Elsevier Inc. All rights reserved.