1139 - 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

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Tomomi Date1, Yukihiko Aikawa1, Akira Hashiramoto2, Tetsuya Yamamoto1, Masaaki Mikami1, Hirokazu Narita1, Shuichi Hirono3 and Shunichi Shiozawa2, 1Research Laboratories, Toyama Chemical Co., Ltd, Toyama, Japan, 2Department 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, 3Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan
Presentation Number: 1139

Background/Purpose: 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.

Method: 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.

Result: 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-1β, IL-3, IL-6, IL-12 (p40), G-CSF, KC/groα, MCP-1, MIP-1β, and RANTES] significantly increased compared with those in the normal paws. Especially, the amounts of IL-1β, IL-6, and KC/groα 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-1β, IL-6, and KC/groα within several hours. Eight cytokines/chemokines including TNFα could not be determined in the paws. The significant elevations of the levels of IL-1β, IL-3, IL-6, G-CSF, KC/groα, MCP-1, and MIP-1β were also observed in the sera from the same individuals. The serum levels of IL-1β and KC/groα were significantly decreased by the treatment of T-5224.

Conclusion: 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.


Keywords: cytokines, rheumatoid arthritis (RA), rheumatoid arthritis, animal models and transcription factor

Disclosure: Y. Aikawa, Toyama Chemical Co.,LTD, 3 ; A. Hashiramoto, None; T. Yamamoto, Toyama Chemical Co.,LTD, 3 ; M. Mikami, Toyama Chemical Co.,LTD, 3 ; H. Narita, Toyama Chemical Co.,LTD, 3 ; S. Hirono, None; S. Shiozawa, None.