Amelioration of experimental arthritis by a calpain-inhibitory compound: regulation of cytokine production by E-64-d in vivo and in vitro
1 Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
2 Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan
3 Discovery Pharmacology I Group, Pharmacology and Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd, Osaka, Japan
Correspondence to: H. Yoshifuji; E-mail: yoshifuj{at}kuhp.kyoto-u.ac.jp
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-1ß 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.
Keywords: anti-type II collagen antibody-induced arthritis, calpastatin, IL-6, rheumatoid arthritis
Transmitting editor: M. Miyasaka
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