Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 145 Middle Shan Dong Road, Shanghai 200001, China.
Arthritis Res Ther. 2012 May 2;14(3):R103. doi: 10.1186/ar3828.
Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.
Sixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.
MIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.
Our results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.
糖皮质激素（GC）治疗仍然是改善系统性红斑狼疮（SLE）患者预后的重要手段。然而，一些患者对 GC 治疗没有产生有效的反应，这成为 SLE 缓解的障碍。确定导致类固醇耐药的潜在机制具有重要意义。巨噬细胞移动抑制因子（MIF）因其与 GCs 的相互关系而引起我们的兴趣。在本研究中，我们首次研究了 MIF 是否与 SLE 中的类固醇耐药性相关，并探讨了潜在的作用机制。
招募了 62 例 SLE 患者（40 例类固醇敏感和 22 例类固醇耐药）和 21 名正常对照者。通过 ELISA 法测定血清 MIF 水平。通过 Western 印迹法测定外周血单个核细胞（PBMCs）中的胞质 MIF 和 IκB 表达。通过核抽提物中的 NF-κB 评估电泳迁移率变动分析。应用基因沉默降低类固醇耐药患者 PBMCs 中的 MIF 表达。用不同浓度的重组人 MIF 处理来自类固醇敏感患者的 PBMCs。
与类固醇敏感患者和对照组相比，类固醇耐药患者的血清和 PBMCs 中的 MIF 水平更高。与类固醇敏感组相比，类固醇耐药患者的 NF-κB 水平显著升高，IκB 水平降低。在 MIF 基因沉默后，来自类固醇耐药患者的细胞中的 IκB 水平增加。在类固醇敏感患者中，在 PBMCs 中用更高浓度的重组人 MIF 处理时，从基线开始检测到 IκB 水平降低和 NF-κB 表达增加。用抗 MIF 单克隆抗体处理 PBMCs 不会调节其 IκB 和 NF-κB 的表达。
我们的结果表明，MIF 可能通过影响 NF-κB/IκB 信号级联来在 SLE 中形成类固醇耐药中发挥作用。作为糖皮质激素敏感性的调节剂，MIF 可能是类固醇节省的潜在靶点。
