Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne 3168, Australia.
Am J Pathol. 2010 Nov;177(5):2366-78. doi: 10.2353/ajpath.2010.091204. Epub 2010 Sep 9.
Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of "steroid-sparing" therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1.
阐明调节糖皮质激素（GC）敏感性的因素对于开发包括类风湿关节炎（RA）在内的慢性炎症性疾病的“类固醇节约”疗法是必要的。越来越多的证据表明，巨噬细胞移动抑制因子（MIF）可以抵消 GC 诱导的抗炎介质的产生，包括丝裂原激活蛋白激酶磷酸酶 1（MKP1），这是一种关键的丝裂原激活蛋白激酶信号抑制剂。这一观察结果尚未扩展到人类疾病；分子机制仍不清楚。我们研究了 NURR1，一种在 RA 中过度表达的 GC 反应性转录因子，作为 MIF 信号的靶标。我们揭示了重组 MIF（rMIF）可阻断 RA 成纤维样滑膜细胞（FLS）中 GC 诱导的 MKP1 表达。rMIF 增强了 NURR1 的表达、人工 NBRE（孤儿受体 DNA 结合位点）报告基因的转激活作用，并逆转了 GC 对 NURR1 的抑制作用。在 MIF-/-滑膜的实验性关节炎中，NURR1 的表达减少，沉默 MIF 可减少 RA FLS 的 NURR1 mRNA。与 MKP1 基因上的 NBRE 鉴定一致，异位表达 NURR1 的 FLS 中 MKP1 mRNA 减少，沉默 NURR1 可增强 RA FLS 中 MKP1 mRNA 的表达。rMIF 增强了 MKP1 基因上的 NBRE 结合，并且缺乏 NBRE 可防止 NURR1 对基础和 GC 诱导的 MKP1 转录激活的抑制作用。这项研究定义了 NURR1 为慢性炎症中的一种新型 MIF 靶标，并证明了 NURR1 在调节抗炎介质 MKP1 中的作用。我们提出了一个 MIF-NURR1 信号轴作为调节 GC 敏感性的 MKP1 的调节剂。
