Effect of Nuclear Factor-kB Inhibition on Rheumatoid Fibroblast-like Synoviocytes and Collagen Induced Arthritis

YUKO OKAZAKI, TETSUJI SAWADA, KATSUYA NAGATANI, YOSHINORI KOMAGATA, TETSUFUMI INOUE, SUSUMU MUTO, AKIKO ITAI, and KAZUHIKO YAMAMOTO

ABSTRACT.

Objective. The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis.

Methods. We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice.

Results. IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice.

Conclusion. Based on these results, IMD-0560 could be a new therapeutic agent for RA. (J Rheumatol 2005;32:1440-7)

Key Indexing Terms:

COLLAGEN-INDUCED ARTHRITIS
NUCLEAR FACTOR-kB
RHEUMATOID ARTHRITIS
FIBROBLAST-LIKE SYNOVIOCYTES

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From the Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo; the Health Administration Center, Tokyo University of Foreign Studies; and the Institute of Medicinal Molecular Design, Tokyo, Japan.

Supported in part by grant 15591051 from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Y. Okazaki, MD, Graduate Student; T. Sawada, MD, PhD, Instructor; K. Nagatani, MD, PhD, Instructor; Y. Komagata, MD, Instructor, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo; T. Inoue, MD, PhD, Professor, Health Administration Center, Tokyo University of Foreign Studies; S. Muto, PhD, General Manager, Drug Discovery Department; A. Itai, PhD, President, Institute of Molecular Design, Inc.; K. Yamamoto, MD, PhD, Professor, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo.

Address reprint requests to Dr. Y. Okazaki, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655. E-mail: okazaki@tkf.att.ne.jp

Accepted for publication March 30, 2005.

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