Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters
Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters
复制标题
DOI：
10.1002/glia.20673
复制
发表时间：
2008-07-01
期刊：
影响因子：
6.2
通讯作者：
Peers, Chris
中科院分区：
文献类型：
--
作者：
Boycott, Hannah E.;Wilkinson, Jenny A.;Peers, Chris
转运蛋白介导的谷氨酸摄取是星形胶质细胞的主要功能。我们之前的研究表明，在缺氧条件下，这一过程通过NF-kappa B介导的谷氨酸转运体EAAT-1和EAAT-2的表达抑制而受到损害。在这里，我们证明了相同的缺氧条件（1% o - 2,24小时）导致星形胶质细胞TNF α产生的急剧增加，而不改变其生存能力。在三种机制不同的nf - κ B抑制剂的存在下，这种缺氧引起的TNF α的产生被阻止。经Western blotting检测，外源性应用TNF α对EAAT-1表达无影响，但模拟缺氧抑制EAAT-2表达的作用。此外，抑制TNF α产生的沙利度胺对缺氧抑制EAAT-1无影响，但对缺氧抑制EAAT-2有抑制作用。这些数据表明，缺氧对星形胶质细胞中谷氨酸转运蛋白表达的调节是亚型特异性的。EAAT-1和EAAT-2的调控都是由NF-kappa B介导的，这种转录调节因子也是增加TNF α产生所必需的。然而，尽管TNF α对缺氧抑制EAAT-2至关重要，但缺氧调节EAAT-1的表达不受该细胞因子的影响。(C) 2008 Wiley-Liss, Inc。
Transporter-mediated glutamate uptake is a principal function of astrocytes. Our previous studies have shown that this process is compromised under hypoxic conditions through the NF-kappa B mediated inhibition of expression of the glutamate transporters EAAT-1 and EAAT-2. Here, we demonstrate that identical conditions of hypoxia (1% O-2, 24 h) lead to a dramatic increase in TNF alpha production from astrocytes without altering their viability. This hypoxia-evoked production of TNF alpha was prevented in the presence of any of three mechanistically distinct NF-kappa B inhibitors. Exogenous application of TNF alpha was without effect on EAAT-1 expression as determined by Western blotting, but mimicked the effects of hypoxia to suppress expression of EAAT-2. Furthermore thalidomide, which prevents TNF alpha production, was without effect on hypoxic suppression of EAAT-1 but prevented hypoxic suppression of EAAT-2. These data indicate that regulation of glutamate transporter expression in astrocytes by hypoxia is subtype specific. Regulation of both EAAT-1 and EAAT-2 is mediated by NF-kappa B, and this transcriptional regulator is also required for increased production of TNF alpha. However, while TNF alpha is essential for hypoxic suppression of EAAT-2, hypoxic modulation of EAAT-1 expression is unaffected by this cytokine. (C) 2008 Wiley-Liss, Inc.