• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>American Journal of Physiology >Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor.
【24h】

Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor.

机译：缺乏维生素D受体的成纤维细胞中NF-κB活性增加。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR-/- mice, the basal level of kappaB inhibitor (IkappaB) alpha protein was markedly decreased compared with VDR+/- MEFs; however, degradation of IkappaBalpha and its phosphorylation in response to TNF-alpha treatment or Salmonella infection were not altered in VDR-/- cells, neither were the levels of IkappaB kinase-alpha and IkappaB kinase-beta proteins. Consistent with IkappaBalpha reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR-/- cells. In addition, the physical interaction between VDR and p65 was absent in VDR-/- MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-kappaB transcriptional activity; consistently, induction of IL-6 by TNF-alpha or IL-1beta was much more robust in VDR-/- than in VDR+/- cells, indicating that VDR-/- cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-kappaB activity. The reduction of IkappaBalpha in VDR-/- MEFs may be partially explained by the lack of VDR-mediated stabilization of IkappaBalpha by 1,25(OH)2D3. This is supported by the observation that IkappaBalpha degradation induced by TNF-alpha was inhibited by 1,25(OH)2D3 in VDR+/- cells, but not in VDR-/- cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-kappaB activation.
机译：已知1,25-二羟基维生素D [1,25（OH）2D3]具有抗炎活性;但是，分子机制仍然不清楚。在这里，我们显示核维生素D受体（VDR）直接参与了NF-κB激活的调节，NF-κB激活是炎症反应必不可少的途径。在源自VDR-/-小鼠的小鼠胚胎成纤维细胞（MEF）中，与VDR +/- MEF相比，κB抑制剂（IkappaB）α蛋白的基础水平显着降低。但是，在TNF-α处理或沙门氏菌感染中，IkappaBalpha的降解及其磷酸化在VDR-/-细胞中没有改变，IkappaB激酶-α和IkappaB激酶-β蛋白的水平也没有改变。与IkappaBalpha减少一致，在未刺激的VDR-/-细胞中，p65在细胞核中的积累显着增加。此外，VDR-/-MEF中不存在VDR和p65之间的物理相互作用，这可能会使p65释放并增加其活性。因此，这些改变共同导致了核p65 DNA结合和NF-κB转录活性的显着增加。始终如一地，TNF-α或IL-1β诱导的IL-6在VDR-/-细胞中比在VDR +/-细胞中更坚固，表明VDR-/-细胞更容易受到炎症刺激。因此，由于固有的高NF-kappaB活性，缺乏VDR的细胞似乎更具促炎性。 VDR-/-MEF中IkappaBalpha的减少可能部分是由于1,25（OH）2D3缺乏VDR介导的IkappaBalpha稳定。观察到的证据表明，TNF-α诱导的IkappaBalpha降解在VDR +/-细胞中被1,25（OH）2D3抑制，但在VDR-/-细胞中没有被抑制。综上，这些数据表明，VDR在调节NF-κB活化中起抑制作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号