糖皮质激素的抗炎作用:分子机制。
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巴恩斯PJ
糖皮质激素的抗炎作用:分子机制。
Sci (Lond)。1998年6月,94 (6):557 - 72。
- PubMed ID
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9854452 (在PubMed]
- 文摘
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1。糖皮质激素被广泛用于抑制炎症的慢性炎性疾病,如哮喘、类风湿性关节炎、炎症性肠道疾病和自身免疫性疾病,所有这些都是与炎症基因的表达增加有关。的分子机制参与这个讨论了糖皮质激素的抗炎作用,尤其是哮喘,占最高的临床使用这些代理。2。糖皮质激素与糖皮质激素受体结合在细胞质中然后二聚,把原子核,它们绑定到糖皮质激素反应元素(GRE) glucocorticoid-responsive基因,导致增加转录。糖皮质激素可能增加抗炎的转录的基因编码蛋白,包括lipocortin-1、白细胞介素- 10”,受体拮抗剂及中性肽链内切酶,但这是不太可能占所有广泛的糖皮质激素的抗炎作用。3所示。最引人注目的糖皮质激素的作用是抑制多种炎症基因的表达(细胞因子、酶、受体和粘附分子)。这不能由于糖皮质激素受体和GRE考试之间的直接交互,因为这些结合位点缺席大部分炎性基因的启动子区域。这更可能是由于直接抑制激活糖皮质激素受体之间的相互作用和激活转录因子,如核能factor-kappa B和激活蛋白1,调节炎症基因的表达。 4. It is increasingly recognized that glucocorticoids change the chromatin structure. Glucocorticoid receptors also interact with CREB-binding protein (CBP), which acts as a co-activator of transcription, binding several other transcription factors that compete for binding sites on this molecule. Increased transcription is associated with uncoiling of DNA wound around histone and this is secondary to acetylation of the histone residues by the enzymic action of CBP. Glucocorticoids may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression. 5. Rarely patients with chronic inflammatory diseases fail to respond to glucocorticoids, although endocrine function of steroids is preserved. This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). 'Dissociated' steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-kappa B, are also targets for novel anti-inflammatory therapies.
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