A plant-derived ligand favoring monomeric glucocorticoid receptor conformation with impaired transactivation potential attenuates collagen-induced arthritis
A plant-derived ligand favoring monomeric glucocorticoid receptor conformation with impaired transactivation potential attenuates collagen-induced arthritis
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DOI：
10.4049/jimmunol.180.4.2608
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Elewaut, Dirk
中科院分区：
文献类型：
--
作者：
Dewint, Pieter;Gossye, Valerie;Elewaut, Dirk
糖皮质激素受体（glucocorticoid receptor，GR）是一种转录因子，通过直接与靶基因启动子结合，或通过干扰参与促炎基因表达的转录因子的活性，对靶基因进行正向调节或负向调节。糖皮质激素的众所周知的不良反应被认为主要是由其GR介导的基因激活特性引起的。虽然GR的二聚化被认为是基因激活特性所必需的，但尚未描述选择性地施加GR单体形成和干扰其他转录因子的化合物。在本研究中，我们报告GR结合，植物衍生的化合物具有显着的解离特性，类风湿性关节炎成纤维细胞样滑膜细胞，这是重要的效应细胞在炎症和基质降解类风湿性关节炎。此外，这些发现可以在小鼠胶原诱导的关节炎中在体内扩展，其中关节炎症被显著抑制而不诱导高胰岛素血症。因此，我们得出结论，GR单体足以抑制体内炎症。
The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of target genes, or negatively by the interference with the activity of transcription factors involved in proinflammatory gene expression. The well-known adverse effects of glucocorticoids are believed to be mainly caused by their GR-mediated gene-activating properties. Although dimerization of GR is thought to be essential for gene-activating properties, no compound has yet been described which selectively imposes GR monomer formation and interference with other transcription factors. In the present study, we report on a GR-binding, plant-derived compound with marked dissociative properties in rheumatoid arthritis fibroblast-like synoviocytes, which are important effector cells in inflammation and matrix degradation in rheumatoid arthritis. In addition, these findings could be extended in vivo in murine collagen-induced arthritis, in which joint inflammation was markedly inhibited without inducing hyperinsulinemia. Therefore, we conclude that GR monomers are sufficient for inhibition of inflammation in vivo.