Stahn Cindy, Löwenberg Mark, Hommes Daniel W, Buttgereit Frank
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Schumannstrasse 20/21, 10117 Berlin, Germany.
Mol Cell Endocrinol. 2007 Sep 15;275(1-2):71-8. doi: 10.1016/j.mce.2007.05.019. Epub 2007 Jun 2.
Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention to the development of optimized glucocorticoids and SEGRAs.
糖皮质激素（GC）是治疗风湿性疾病和其他炎症性疾病时最常用的抗炎和免疫抑制药物。其治疗作用被认为是由四种不同的作用机制介导的：由胞质糖皮质激素受体（cGCR）引起的经典基因组作用机制；同样由cGCR引发的继发性非基因组效应；膜结合糖皮质激素受体（mGCR）介导的非基因组效应；与细胞膜相互作用引起的非特异性、非基因组效应。GC作用的经典基因组机制可分为两个过程：“转抑制”，它负责大量理想的抗炎和免疫调节作用；以及“转激活”，它与频繁出现的副作用以及一些免疫抑制活性相关[埃尔琴，J.，施泰因米勒，L.，巴尔齐克，K.，滕布罗克，K.，纳肯，W.，艾森纳赫，M.，诺德休斯，U.，索尔格，C.，松德科特，C.，罗斯，J.，2007年。糖皮质激素诱导人单核细胞特异性活化的抗炎亚型分化。《血液》109卷，第1265 - 1274页]。人们已经做出了巨大努力来减少糖皮质激素引起的不良反应，但传统糖皮质激素的改进几乎已达到极限。因此，正在测试传统“老药”的新变体，硝基类固醇和长效循环脂质体糖皮质激素确实显示出有希望的结果。然而，关键问题应该是设计全新的药物，如选择性糖皮质激素受体激动剂（SEGRA）。这些创新的甾体或非甾体分子诱导转抑制，而转激活过程受影响较小。关于两种不同的GCR配体A276575和ZK216348的初步报告显示出有希望的结果。在此，我们综述上述糖皮质激素作用机制，并特别关注优化糖皮质激素和SEGRA的开发。
