Transcription factor NF-κB is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-α or interleukin-1β
Transcription factor NF-κB is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-α or interleukin-1β
复制标题
DOI：
10.1074/jbc.m107515200
复制
发表时间：
2002-02-22
影响因子：
4.8
通讯作者：
Greenberg, BH
中科院分区：
文献类型：
--
作者：
Cowling, RT;Gurantz, D;Greenberg, BH
肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β上调培养的新生大鼠心脏成纤维细胞中1型血管紧张素II受体（AT（1））mRNA和蛋白药理学抑制剂和抗降解突变体IkappaB-α的使用表明，转录因子核因子-kappaB（NF-κ B）是必不可少的精氨酸诱导的AT，上调。TNF-α处理后AT（1）mRNA的增加缓慢，6-12 h达到显著性，24-48 h达到峰值。电泳迁移率改变分析显示，单剂量TNF-α可维持NF-κ B核转位大于或等于24小时。由于延长的NF-κ B活化似乎是使AT（1）上调最大化所必需的，因此进一步研究了持续NF-κ B活化的机制。用TNF-α刺激诱导IkappaB激酶（IKK）活性增加> 10倍，20分钟后迅速降低。在此期间，IkappaB-α和IkappaB-β蛋白被降解，随后通过NF-κ B依赖性转录重新合成IkappaB-α。然而，IkappaB亚型和IKK活性没有完全返回到未刺激的值在12小时的时间过程中。这些结果表明，低但持续的IKK活性和IkappaB降解导致延长NF-κ B核转位和最大AT（1）上调持续存在的TNF-α。
Tumor necrosis factor-a (TNF-alpha) and interleukin-1beta up-regulate type 1 angiotensin IIreceptor (AT(1)) mRNA and protein in cultured neonatal rat cardiac fibroblasts. The use of pharmacologic inhibitors and a degradation-resistant mutant IkappaB-alpha demonstrated that the transcription factor nuclear factor-kappaB (NF-kappaB) is necessary for cytokine-induced AT, up-regulation. The increase in AT(1) mRNA with TNF-alpha treatment is slow, reaching Significance by 6-12 h and peaking by 24-48 h. Electrophoretic mobility shift assays revealed that NF-kappaB nuclear translocation was maintained for greater than or equal to24 h with a single dose of TNF-alpha. Since prolonged NF-KB activation appeared necessary to maximize AT(1) up-regulation, the mechanism of persistent NF-kappaB activation was studied further. Stimulation with TNF-alpha induced a >10x increase in IkappaB kinase (IKK) activity that quickly diminished by 20 min. IkappaB-alpha and IkappaB-beta proteins were degraded during this time, and IkappaB-alpha was resynthesized subsequently by NF-kappaB-dependent transcription. However, IkappaB isoforms and IKK activity did not return completely to unstimulated values during a 12-h time course. These results suggest that low but persistent IKK activity and IkappaB degradation lead to prolonged NF-kappaB nuclear translocation and maximal AT(1) up-regulation in the continued presence of TNF-alpha.