摘要
内源性糖皮质激素产生多样化的生理过程,包括调节和抗炎反应,并在炎症和自身免疫性疾病的发病机制中起重要作用。糖皮质激素调节炎症过程存在于下丘脑-垂体-肾上腺轴激素的反馈电路、局部控制、细胞类型和特定情境的局部调节系统等方面。在组织水平上,糖皮质激素的敏感性和反应性是由多种因素决定的:包括输送糖皮质激素血液的局部性,形成具有生物活性的糖皮质激素(合成代谢11β-羟类固醇脱氢酶酶)局部性,糖皮质激素受体(GR)的数量和功能和GR亲和力的配体的局限性。众多的分子因素通过影响GR影响糖皮质激素反应的敏感性,细胞因子是其主要成分,它能通过对GR功能的抑制,增强抗糖皮质激素。GR亚型,由选择性剪接、翻译和翻译后修饰所产生,是调节糖皮质激素的进一步机制。GR编码基因的遗传变异是其他可能影响自身免疫性疾病的易感性和严重性的潜在因素,可能在药物的个体反应中起关键作用。在本文中,我们旨在总结细胞类型特异性糖皮质激素信号和局部免疫系统之间的联系。预测个体类固醇敏感性和识别糖皮质激素抵抗发展的关键成分在个性化治疗中是必不可少的。局部或特定组织糖皮质激素信号传导和细胞因子的影响均可能决定炎症反应的大小,也可能与含糖皮质激素的治疗策略成功有关。
关键词: 11β-羟类固醇脱氢酶酶,自身免疫性疾病,糖皮质激素受体
Current Medicinal Chemistry
Title:Tissue-specific Glucocorticoid Signaling May Determine the Resistance Against Glucocorticoids in Autoimmune Diseases
Volume: 22 Issue: 9
Author(s): A. Szappanos, Z. Nagy, B. Kovacs, G. Poor, M. Toth, K. Racz, E. Kiss and A. Patocs
Affiliation:
关键词: 11β-羟类固醇脱氢酶酶,自身免疫性疾病,糖皮质激素受体
摘要: Endogenous glucocorticoids exert a diverse array of physiological processes including immunemodulatory or anti-inflammatory responses and play an important role in the pathogenesis of inflammatory and autoimmune diseases. Regulation of inflammatory processes by glucocorticoids is controlled in a cytokinehypothalamo- pituitary-adrenal axis feedback circuit and on the local, cell-type and context-specific local regulatory system. At the tissue level the sensitivity and response to glucocorticoids are determined by multiple factors: including the local availability to glucocorticoids transported by blood, the locally-formed bioactive glucocorticoids (synthesized and metabolized 11β-hydroxysteroid dehydrogenase enzymes), the number and function of the glucocorticoid receptor (GR) and the GR affinity to its ligands. Numerous molecular factors are known to influence the sensitivity of glucocorticoid response through the GR. Cytokines are one of the major components that can inhibit GR function and can potentiate the resistance against glucocorticoids. GR isoforms, generated by alternative splicing, alternative translation and posttranslation modification are further mechanisms which modulate glucocorticoid signaling. Genetic variants within the GR encoding gene are other potential factors that may influence the susceptibility and severity of autoimmune disorders and may play a key role in individual response to medication. In this review our aim was to summarize our knowledge about the connections between the cell type-specific glucocorticoid signaling and the local immune system. Prediction of individual sensitivity to steroids and identification of key players in development of glucocorticoid resistance are essential in individualized therapies. The local, tissue-specific glucocorticoid signaling and its influence by cytokines may be important in determining the magnitude of inflammatory reactions, and may also be related to the success of glucocorticoidcontaining therapeutic strategies.
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A. Szappanos, Z. Nagy, B. Kovacs, G. Poor, M. Toth, K. Racz, E. Kiss and A. Patocs , Tissue-specific Glucocorticoid Signaling May Determine the Resistance Against Glucocorticoids in Autoimmune Diseases, Current Medicinal Chemistry 2015; 22 (9) . https://dx.doi.org/10.2174/0929867321666141216125012
DOI https://dx.doi.org/10.2174/0929867321666141216125012 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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