Molecular mechanisms of immunosuppression and anti-inflammatory activities by glucocorticoids
Molecular mechanisms of immunosuppression and anti-inflammatory activities by glucocorticoids
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DOI：
10.1164/ajrccm/154.2_pt_2.s11
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发表时间：
1996-08-01
影响因子：
24.7
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Didonato, JA;Saatcioglu, F;Karin, M
糖皮质激素（OC）是炎症的生理抑制剂，几十年来一直用作免疫抑制剂（1，2）。尽管它们在治疗各种炎症性疾病（如哮喘、类风湿性关节炎、系统性红斑狼疮和其他自身免疫性疾病）方面具有广泛的疗效（3，4），但多年来对OC治疗作用的分子机制知之甚少。然后，受体-受体复合物易位到细胞核，在那里它与称为激素反应元件（HRE）的顺式作用DNA序列结合，并调节特定靶基因的转录（在参考文献5中综述）。配体OCR与DNA的结合通常导致通过阳性HRE（pHRE）激活转录，但与不太常见的所谓阴性HRE（nHRE）的结合可导致转录抑制。然而，近年来，发现OCR可以以依赖于HRE的方式调节转录，不是通过直接结合HRE，而是通过干扰其他转录因子的活性，例如CREB（6，7）、AP-1（参考文献5中综述）和NF-κ B（8-13），其活性响应于细胞表面受体接收的细胞外信号而被调节。OCR的这些新发现的活性是极其重要的，因为它们一方面提供OC与另一方面多肽激素和细胞因子之间的串扰。这种形式的交叉偶联对于维持细胞内稳态可能是必不可少的，并且提供对各种生理过程的微调，例如分化、细胞增殖以及炎症和免疫应答。经受这种交叉偶联的一些基因包括金属蛋白酶，如基质溶解素和胶原酶，以及许多细胞因子，如白细胞介素-2（IL-2）。OC对这些基因的抑制可能是这些激素抗关节炎和免疫抑制作用的基础（8，9）。金属蛋白酶的表达是类风湿性关节炎和其他自身免疫性疾病中组织破坏的原因（3），而细胞因子及其受体（其中一些也是交叉偶联的靶点，例如IL-2受体）的表达对于免疫和炎症反应的启动和维持至关重要。在急性炎症或各种免疫病症期间发生这些基因的失调表达，其中许多基因被转录因子AP-1（14）和NF-κ B（15）激活，OC提供了一种非常有效的手段来减少它们的表达，从而防止疾病进展。本文综述了OC对转录因子AP-1和NF-κ B激活的基因的抑制作用的分子机制。
Olucocorticoids (OCs) are physiologic inhibitors of inflammation and have been used for decades as immunosuppressive agents (1, 2). Despite their wide therapeutic efficacy in the treatment of a variety of inflammatory diseases, such as asthma, rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune disease (3, 4), the molecular mechanisms that underlie the therapeutic affects of OCs were for many years poorly understood.On entering the cell, OCs bind to a cytoplasmic glucocorticoid receptor (OCR), a member of the nuclear receptor superfamily. The hormone-receptor complex then translocates to the nucleus, where it binds to cis-acting DNA sequences, known as hormone response elements (HREs), and modulates transcription of specific target genes (reviewed in reference 5). Binding of the liganded OCR to DNA usually results in activation of transcription through positive HREs (pHREs), but binding to less common so-called negative HREs (nHREs) can result in repression of transcription. In recent years, however, it was found that OCR can modulate transcription in a hormone-dependent manner, not through direct binding to HREs, but through interference with the activity of other transcription factors, such as CREB (6, 7), AP-l (reviewedin reference 5), and NF-KB (8-13), whose activity is regulated in response to extracellular signals received by cell surface receptors. These newly discovered activities of the OCR are extremely important because they provide cross-talk between OCs on one hand and polypeptide hormones and cytokines on the other hand. This form of cross-coupling is likely to be essential for maintenance of cellular homeostasis and provides fine tuning to a variety of physiologic processes, such as differentiation, cell proliferation, and inflammatory and immune responses. Some of the genes that are subject to this crosscoupling include metalloproteinases, such as stromelysin and collagenase, and many cytokines, such as interleukin-2 (lL-2). The repression of such genes by OCs is likely to underlie the antiarthritic and immunosuppressive effects of these hormones (8, 9). The expression of metalloproteinases is the cause for tissue destruction in rheumatoid arthritis and other autoimmune disorders (3), while the expression of cytokines and their receptors (some of which are also the target of cross-coupling, eg, IL-2 receptors) are essential for initiation and maintenance of immune and inflammatory responses. Deregulated expression of such genes, many of which are activated by transcription factors AP-l (14) and NF-KB (15), occurs during acute inflammation or various immune disorders, and OC provides a very effective means to curtail their expression and thus prevent disease progression. The purpose of the reviewis to describe the molecular mechanisms that may account for the potent repressiveeffects of OCs on genes that are activated by transcription factors AP-I and NF-KB.