Astrocyte Reactivity to Unconjugated Bilirubin Requires TNF-α and IL-1β Receptor Signaling Pathways
Astrocyte Reactivity to Unconjugated Bilirubin Requires TNF-α and IL-1β Receptor Signaling Pathways
复制标题
DOI：
10.1002/glia.21072
复制
发表时间：
2011-01-01
期刊：
影响因子：
6.2
通讯作者：
Brites, Dora
中科院分区：
文献类型：
--
作者：
Fernandes, Adelaide;Barateiro, Andreia;Brites, Dora
黄疸和败血症是新生儿常见的疾病，可导致神经发育后遗症，即如果同时存在的话。我们已经报道，肿瘤坏死因子-α和白介素1-β是由培养的神经元产生的，主要是由暴露于未结合胆红素(UCB)的胶质细胞产生的。这些细胞因子的作用是由细胞表面受体通过核因子-kappaB依赖的途径介导的，我们已经证明该途径可被脐带血激活。本研究旨在探讨肿瘤坏死因子-α和白介素1-β信号在大鼠大脑皮层星形胶质细胞对脐带血反应中的作用。星形胶质细胞暴露于脐带血后，肿瘤坏死因子受体(TNFR)1和白介素1β受体(IL-1R)1的表达均增加，但TNFR2的表达和活化无明显变化，受体分子接头TRAF2和TRAF6的结合增强。使用siRNA技术沉默TNFR1，或使用其内源性拮抗剂IL-1受体拮抗剂(IL-1ra)阻断IL-1β级联反应，可阻止脐血诱导的细胞因子释放和核因子-kappaB的激活。有趣的是，缺乏TNF-α信号转导在短时间内减少了UCB诱导的细胞死亡，尽管在长期暴露后观察到了增加；相反，抑制IL-1β级联反应产生了UCB对星形胶质细胞损伤的持续阻断。总之，我们的数据显示，在体外将大鼠皮质星形胶质细胞暴露于UCB时，炎症通路被激活，并且这种激活随着时间的延长而延长。这支持了炎症途径在UCB脑损伤中发挥作用的概念，并且它们可能是重要的药理靶点。(C)2010年Wiley-Liss公司
Jaundice and sepsis are common neonatal conditions that can lead to neurodevelopment sequelae, namely if present at the same time. We have reported that tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta are produced by cultured neurons and mainly by glial cells exposed to unconjugated bilirubin (UCB). The effects of these cytokines are mediated by cell surface receptors through a nuclear factor (NF)-kappa B-dependent pathway that we have showed to be activated by UCB. The present study was designed to evaluate the role of TNF-alpha and IL-1 beta signaling on astrocyte reactivity to UCB in rat cortical astrocytes. Exposure of astrocytes to UCB increased the expression of both TNF-alpha receptor (TNFR) 1 and IL-1 beta receptor (IL-1R) 1, but not TNFR2, as well as their activation, observed by augmented binding of receptors' molecular adaptors, TRAF2 and TRAF6, respectively. Silencing of TNFR1, using siRNA technology, or blockade of IL-1 beta cascade, using its endogenous antagonist, IL-1 receptor antagonist (IL-1ra), prevented UCB-induced cytokine release and NF-kappa B activation. Interestingly, lack of TNF-alpha signal transduction reduced UCB-induced cell death for short periods of incubation, although an increase was observed after extended exposure; in contrast, inhibition of IL-1 beta cascade produced a sustained blockade of astrocyte injury by UCB. Together, our data show that inflammatory pathways are activated during in vitro exposure of rat cortical astrocytes to UCB and that this activation is prolonged in time. This supports the concept that inflammatory pathways play a role in brain damage by UCB, and that they may represent important pharmacological targets. (C) 2010 Wiley-Liss, Inc.