Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin
Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin
复制标题
DOI：
10.1111/j.1471-4159.2006.03680.x
复制
发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Brites, D
中科院分区：
文献类型：
--
作者：
Fernandes, A;Falcao, AS;Brites, D
在新生儿高胆红素血症时，未结合胆红素（UCB）激活的星形胶质细胞可能通过产生细胞因子参与脑毒性。作为解决涉及UCB诱导的星形胶质细胞免疫反应的信号转导级联反应的第一步，我们测试了肿瘤坏死因子（TNF）-α受体1（TNFR 1），丝裂原活化蛋白激酶（MAPK）和核因子κ B（NF-κ B）是否会在暴露于UCB的星形胶质细胞中被激活，并检查细胞因子产生的概况。用UCB刺激的星形胶质细胞培养物显示TNFR 1蛋白水平迅速升高，随后激活MAPK p38、Jun N末端激酶1/2和细胞外信号调节激酶1/2以及NF-κ B。有趣的是，这些信号效应物的诱导先于TNF-α和白细胞介素（IL）-1 β mRNA的早期上调，以及随后TNF-α、IL-1 β和IL-6的分泌。用UCB处理星形胶质细胞也诱导细胞死亡，其水平与星形胶质细胞暴露于重组TNF-α和IL-1 β后获得的水平相当。此外，当NF-κ B信号转导通路被抑制时，细胞活力和细胞因子分泌的损失减少，表明NF-κ B在星形胶质细胞对UCB的反应中起关键作用。这些结果表明，在高胆红素血症的细胞损伤的分子机制的复杂性，并提供了一个新的治疗策略的发展基础。
During neonatal hyperbilirubinaemia, astrocytes activated by unconjugated bilirubin (UCB) may contibute to brain toxicity through the production of cytokines. As a first step in addressing the signal transduction cascades involved in the UCB-induced astroglial immunological response, we tested whether tumour necrosis factor (TNF)-alpha receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa B) would be activated in astrocytes exposed to UCB, and examined the profile of cytokine production. Astrocyte cultures stimulated with UCB showed a rapid rise in TNFR1 protein levels, followed by activation of the MAPKs p38, Jun N-terminal kinase1/2 and extracellular signal-regulated kinase1/2, and NF-kappa B. Interestingly, the induction of these signal effectors preceded the early up-regulation of TNF-alpha and interleukin (IL)-1 beta mRNAs, and later secretion of TNF-alpha, IL-1 beta and IL-6. Treatment of astrocytes with UCB also induced cell death, with levels comparable to those obtained after exposure of astrocytes to recombinant TNF-alpha and IL-1 beta. Moreover, loss of cell viability and cytokine secretion were reduced when the NF-kappa B signal transduction pathway was inhibited, suggesting a key role for NF-kappa B in the astroglial response to UCB. These results demonstrate the complexity of the molecular mechanisms involved in cell injury by UCB during hyperbilirubinaemia and provide a basis for the development of novel therapeutic strategies.