Norepinephrine increases IκBα expression in astrocytes
Norepinephrine increases IκBα expression in astrocytes
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DOI：
10.1074/jbc.m203256200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Feinstein, DL
中科院分区：
文献类型：
--
作者：
Gavrilyuk, V;Dello Russo, C;Feinstein, DL
神经递质去甲肾上腺素（NE）可以抑制胶质细胞中炎症基因的表达，但其机制尚不清楚。在原代星形胶质细胞中，NE剂量依赖性地增加抑制性IkappaB α蛋白的表达，伴随着IkappaB α mRNA稳态水平的增加。在30-60分钟时观察到mRNA的最大增加，在4小时时观察到蛋白质的最大增加，这些作用是由NE与β-肾上腺素能受体结合介导的。NE激活了转染到星形胶质细胞或C6胶质瘤细胞中的1.3-磷酸酶IkappaB α启动子，这种激活被β-拮抗剂和蛋白激酶A抑制剂阻止，但不被NF κ B抑制剂阻止。NE增加了IkappaB α蛋白在胞浆和核组分，这表明增加了核摄取的IkappaB α。在正常成年大鼠的额叶皮质中检测到IkappaB α，并且如果通过损伤蓝斑使中枢NE水平耗尽，则IkappaB α水平降低。脑IkappaB α水平的降低被脂多糖增加的炎症反应所抵消。这些结果表明，IkappaB α的表达调节NE在转录和转录后水平，这可能有助于观察到的NE在体外和体内的抗炎特性。
The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory IkappaBalpha protein accompanied by an increase in steady state levels of IkappaBalpha mRNA. Maximal increases were observed at 30-60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to beta-adrenergic receptors. NE activated a 1.3-kilobase IkappaBalpha promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a beta-antagonist and by protein kinase A inhibitors but not by an NFkappaB inhibitor. NE increased IkappaBalpha protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of IkappaBalpha. IkappaBalpha was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain IkappaBalpha levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that IkappaBalpha expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.