Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Inhibitory Effect of c-Fos/AP-1 Inhibitor T-5224 on the Levels of Cytokines and Chemokines in the Arthritic Lesion of Mice with Collagen-Induced Arthritis.
Date1, Tomomi, Aikawa1, Yukihiko, Hashiramoto2, Akira, Yamamoto1, Tetsuya, Mikami1, Masaaki, Narita1, Hirokazu, Hirono3, Shuichi
Research Laboratories, Toyama Chemical Co., Ltd, Toyama, Japan
Department of Biophysics, Kobe University Graduate School of Health Sciences/Department of Medicine, Kobe University Graduate School of Medicine/The Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan
Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan
Activator protein-1 (AP-1) directly regulates the expressions of inflammatory cytokines and matrix-degrading matrix metalloproteinases important in rheumatoid arthritis (RA). We have previously reported that a small molecule c-Fos/AP-1 inhibitor T-5224 prevented the development of arthritis and joint destruction in mice with collagen-induced arthritis (CIA). The purpose of this study was to investigate its effect on the expression profile of cytokines and chemokines in the arthritic hind paw of mice with CIA after a single administration of T-5224.
CIA was induced in DBA/1J mice by the immunization with bovine type II collagen twice on day 0 and 21. On day 35, hind paws and serum were collected at 0, 1, 3, and 6 hours after a single oral administration of 30 mg/kg of T-5224. The tissue extracts were prepared from each paw. The amounts of 23 cytokines/chemokines in the tissue extracts and sera were measured using Bio-Plex Mouse Cytokine 23-Plex Panel or ELISA.
The arthritis developed from several days after the secondary immunization, and mice showed severe arthritis on day 35. When analyzing each of hind paws with full-blown arthritis, the levels of 9 cytokines/chemokines [IL-1b, IL-3, IL-6, IL-12 (p40), G-CSF, KC/groa, MCP-1, MIP-1b, and RANTES] significantly increased compared with those in the normal paws. Especially, the amounts of IL-1b, IL-6, and KC/groa in the arthritis hind paws were approximately 40 times higher than those in normal paws. A single administration of T-5224 at the dose of 30 mg/kg significantly decreased the levels of IL-1b, IL-6, and KC/groa within several hours. Eight cytokines/chemokines including TNFa could not be determined in the paws. The significant elevations of the levels of IL-1b, IL-3, IL-6, G-CSF, KC/groa, MCP-1, and MIP-1b were also observed in the sera from the same individuals. The serum levels of IL-1b and KC/groa were significantly decreased by the treatment of T-5224.
T-5224 immediately reduced the levels of inflammatory cytokines and chemokines in the arthritic lesion. The results suggest that the prompt inhibitory effect of T-5224 on the overexpression of cytokines and chemokines contributes to the anti-arthritic effects in the therapy of RA.
To cite this abstract, please use the following information:
Date, Tomomi, Aikawa, Yukihiko, Hashiramoto, Akira, Yamamoto, Tetsuya, Mikami, Masaaki, Narita, Hirokazu, et al; Inhibitory Effect of c-Fos/AP-1 Inhibitor T-5224 on the Levels of Cytokines and Chemokines in the Arthritic Lesion of Mice with Collagen-Induced Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1139