Amelioration of experimental arthritis by a calpain-inhibitory compound:: regulation of cytokine production by E-64-d in vivo and in vitro
Amelioration of experimental arthritis by a calpain-inhibitory compound:: regulation of cytokine production by E-64-d in vivo and in vitro
复制标题
DOI：
10.1093/intimm/dxh311
复制
发表时间：
2005-10-01
影响因子：
4.4
通讯作者：
Mimori, T
中科院分区：
文献类型：
--
作者：
Yoshifuji, H;Umehara, H;Mimori, T
钙蛋白酶是一种钙依赖性半胱氨酸蛋白酶，参与类风湿性关节炎(RA)的病理生理过程。本研究的目的是观察钙蛋白酶抑制化合物对类风湿关节炎动物模型的治疗效果，并阐明其在体内和体外的作用机制。用抗II型胶原单抗和脂多糖诱导BALB/c小鼠关节炎模型，分别给予高剂量(9 mg·kg~(-1)/d)、低剂量(3 mg·kg~(-1)·d)E-(膜通透性半胱氨酸蛋白酶抑制剂)或对照稀释液治疗。结果表明，与对照稀释剂相比，高剂量的E--d可显著减轻关节炎的临床症状和组织病理学改变，而低剂量的E--d的作用不明显。接下来，我们采用定量逆转录-聚合酶链式反应的方法，观察了E--d对炎症关节组织细胞因子基因表达的影响。高剂量E--d可显著降低炎症关节组织中IL-6和IL-1β的表达水平。E--d对滑膜细胞株(E11)和RA患者原始滑膜细胞的调节作用也在体外得到证实。这些结果表明，钙蛋白酶在关节炎的病理生理学中起着关键作用，钙蛋白酶抑制化合物可能适用于类风湿性关节炎等关节炎的治疗。
Calpain, a calcium-dependent cysteine proteinase, has been reported to participate in the pathophysiology of rheumatoid arthritis (RA). The aim of this study is to investigate the therapeutic efficacy of calpain-inhibitory compounds in an animal model of RA and to clarify the underlying mechanisms in vivo and in vitro. Arthritis was induced in BALB/c mice with anti-type II collagen mAbs and LPS, and the mice were treated intra-peritoneally with a high dose (9 mg kg(-1) per day) or low dose (3 mg kg(-1) per day) of E-64-d (a membrane-permeable cysteine proteinase inhibitor) or control diluent. As a result, a high dose of E-64-d significantly alleviated the clinical arthritis and the histopathological findings, compared with the control diluent, although a low dose of E-64-d did not have a significant effect. Next, we evaluated the effects of E-64-d on cytokine mRNA expression at the inflamed joints by quantitative reverse transcription-PCR. High dose of E-64-d significantly decreased IL-6 and IL-1 beta mRNA levels at the inflamed joints. The regulatory effects of E-64-d on cytokine production were also confirmed in vitro, using a synovial cell line (E11) and crude synoviocytes derived from RA patients. These results suggest the key roles of calpain in the pathophysiology of arthritis and that calpain-inhibitory compounds might be applicable to the treatment of arthritic diseases such as RA.