Glucocorticoids and inflammation revisited: The state of the art
Glucocorticoids and inflammation revisited: The state of the art
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DOI：
10.1159/000069969
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发表时间：
2002-01-01
影响因子：
2.4
通讯作者：
Chrousos, G
中科院分区：
文献类型：
--
作者：
Franchimont, D;Kino, T;Chrousos, G
糖皮质激素已被用于治疗炎症和自身免疫性疾病，并防止移植排斥反应超过50年。这些激素通过细胞质、热休克蛋白结合的糖皮质激素受体发挥作用，糖皮质激素受体易位到细胞核中，在细胞核中，它们通过结合特异性启动子DNA序列（反式激活）或通过与转录因子相互作用（反式阻遏）来调节应答基因的转录活性。通过与不同的信号通路相互作用，新鉴定的核受体辅调节因子增强或减弱糖皮质激素的作用，从而解释糖皮质激素的基因、细胞、组织和环境依赖性作用。糖皮质激素调节参与先天性免疫应答引发的基因，而它们对适应性免疫应答的作用是抑制细胞[辅助性T细胞（Th）1-定向]免疫并促进体液（Th 2-定向）免疫和耐受。在过去的十年中，产生了新的见解糖皮质激素的敏感性和抵抗的炎症，自身免疫性和过敏性疾病的机制。炎症刺激的质量和严重程度以及患者的遗传学和体质在这些疾病的糖皮质激素敏感性、依赖性和抵抗性中起关键作用。虽然糖皮质激素增加了对机会性感染的易感性，但在整个疾病过程中以持续方式给药时，它们在存在严重全身性炎症的情况下也非常有益，例如在脓毒性休克和急性呼吸窘迫综合征中观察到的炎症。糖皮质激素通过与免疫调节不同的分子机制产生其心血管、代谢和抗生长副作用。幸运的是，第一代组织和免疫与心血管/代谢效应选择性糖皮质激素可用于研究和进一步改进。“设计师”糖皮质激素有望成为炎症性疾病治疗的一个新的重大进展。版权所有（C）2003 S. Karger AG，巴塞尔。
Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue- and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue- and immune- versus cardiovascular/ metabolic effect-selective glucocorticoids is available for study and further improvement. 'Designer' glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases. Copyright (C) 2003 S. Karger AG, Basel.