Center for Inflammatory Disease, Monash University Department of Medicine, Monash Medical Center, Block E Level 5, 246 Clayton Road, Clayton, VIC 3168, Australia.
Nat Rev Rheumatol. 2011 Jun;7(6):340-8. doi: 10.1038/nrrheum.2011.59. Epub 2011 May 10.
Glucocorticoids have been exploited therapeutically for more than six decades through the use of synthetic glucocorticoids as anti-inflammatory agents, and are still used in as many as 50% of patients suffering from inflammatory diseases such as rheumatoid arthritis (RA). Better understanding of the mechanisms of action of glucocorticoids could enable the development of therapies that dissociate the broad-spectrum benefits of glucocorticoids from their adverse metabolic effects. The glucocorticoid-induced leucine zipper protein (GILZ; also known as TSC22 domain family protein 3) is a glucocorticoid-responsive molecule whose interactions with signal transduction pathways, many of which are operative in RA and other inflammatory diseases, suggest that it is a key endogenous regulator of the immune response. The overlap between the observed effects of GILZ on the immune system and those of glucocorticoids strongly suggest GILZ as a critical mediator of the therapeutic effects of glucocorticoids. Observations of the immunomodulatory effects of GILZ in human RA synovial cells, and in an in vivo model of RA, support the hypothesis that GILZ is a key glucocorticoid-induced regulator of inflammation in RA. Moreover, evidence that the effect of GILZ on bone loss might be in contrast to those of glucocorticoids suggests manipulation of GILZ as a potential means of dissociating the beneficial anti-inflammatory effects of glucocorticoids from their negative metabolic repercussions.
糖皮质激素已经被广泛应用于临床 60 余年，其人工合成类似物被广泛用于治疗炎症性疾病，如类风湿关节炎（RA），约有 50%的此类患者接受此类药物治疗。如果能更好地了解糖皮质激素的作用机制，就有可能开发出能将其广泛的抗炎作用与其不良代谢作用相分离的治疗方法。糖皮质激素诱导亮氨酸拉链蛋白（GILZ；也称为 TSC22 结构域家族蛋白 3）是一种糖皮质激素反应性分子，它与信号转导途径相互作用，其中许多途径在 RA 和其他炎症性疾病中起作用，这表明它是免疫反应的关键内源性调节剂。GILZ 对免疫系统的观察到的作用与糖皮质激素的作用之间的重叠强烈表明 GILZ 是糖皮质激素治疗效果的关键介质。在人类 RA 滑膜细胞和 RA 体内模型中观察到 GILZ 的免疫调节作用，支持 GILZ 是 RA 中糖皮质激素诱导炎症的关键调节剂的假说。此外，有证据表明 GILZ 对骨丢失的影响可能与糖皮质激素的作用相反，这表明操纵 GILZ 可能是将糖皮质激素的抗炎作用与其负面代谢影响分离的一种潜在手段。
