Suzuki M, Yoshida H, Hashizume M, Tanaka K, Matsumoto Y
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Company Ltd, Gotemba, Shizuoka, Japan.
Clin Exp Immunol. 2015 Nov;182(2):154-61. doi: 10.1111/cei.12685. Epub 2015 Aug 31.
In a mouse arthritis model, we investigated whether interleukin-6 receptor (IL-6R) blockade would enhance the anti-arthritic effect of glucocorticoids (GCs). DBA/1J mice were immunized with type II collagen (CII), and were treated with prednisolone (PSL) and/or anti-mouse IL-6R antibody (MR16-1). Also, the effects of IL-6 on gene expression and the nuclear translocation of glucocorticoid receptors (GRs) were examined in cultured cells treated with dexamethasone (DEX). PSL reduced the arthritis score dose-dependently in the collagen-induced arthritis (CIA) mouse model. The arthritis score in the PSL (3 mg/kg) + MR16-1 group was lower than in the PSL (3 mg/kg) group, and at the same level as in the PSL (6 mg/kg) group. Lumbar vertebra bone mineral density (BMD) was decreased significantly in CIA mice and was higher in the PSL (3 mg/kg) + MR16-1 group than in the PSL (6 mg/kg) group. In the in-vitro synovial cells, IL-6 pretreatment attenuated the inhibitory effect of DEX on cyclooxygenase (COX)-2 expression and inhibited the nuclear translocation of GR induced by DEX. In contrast, in MC3T3-E1 osteoblastic cells, IL-6 pretreatment exacerbated the decrease in expression of osteocalcin and the increase in expression of receptor activator of nuclear factor kappa-B ligand (RANKL) by DEX. We demonstrated that IL-6 signalling blockade by an anti-IL-6R antibody can augment the anti-arthritic effect of GCs and inhibit the bone loss they cause.
在小鼠关节炎模型中，我们研究了白细胞介素-6受体（IL-6R）阻断是否会增强糖皮质激素（GCs）的抗关节炎作用。用II型胶原（CII）免疫DBA/1J小鼠，并用泼尼松龙（PSL）和/或抗小鼠IL-6R抗体（MR16-1）进行治疗。此外，在用地塞米松（DEX）处理的培养细胞中，检测了IL-6对基因表达和糖皮质激素受体（GRs）核转位的影响。在胶原诱导的关节炎（CIA）小鼠模型中，PSL剂量依赖性地降低了关节炎评分。PSL（3mg/kg）+MR16-1组的关节炎评分低于PSL（3mg/kg）组，与PSL（6mg/kg）组处于同一水平。CIA小鼠的腰椎骨矿物质密度（BMD）显著降低，PSL（3mg/kg）+MR16-1组的BMD高于PSL（6mg/kg）组。在体外滑膜细胞中，IL-6预处理减弱了DEX对环氧合酶（COX）-2表达的抑制作用，并抑制了DEX诱导的GR核转位。相反，在MC3T3-E1成骨细胞中，IL-6预处理加剧了DEX引起的骨钙素表达下降和核因子κB受体激活剂配体（RANKL）表达增加。我们证明，抗IL-6R抗体阻断IL-6信号传导可增强GCs的抗关节炎作用，并抑制其引起的骨质流失。
