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Open Access Research article

A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation

Asako Chiba1, Miho Mizuno1, Chiharu Tomi1, Ryohsuke Tajima1, Iraide Alloza2, Alessandra di Penta2, Takashi Yamamura1, Koen Vandenbroeck23 and Sachiko Miyake1*

Author Affiliations

1 Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan

2 Neurogenomiks Laboratory, Universidad Del País Vasco (UPV/EHU), Parque Tecnológico de Bizkaia, 48170 Zamudio, Spain

3 IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

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Arthritis Research & Therapy 2012, 14:R9  doi:10.1186/ar3683

Published: 17 January 2012

Abstract

Introduction

Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis.

Methods

To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) in Freund's adjuvant. Collagen antibody-induced arthritis (CAIA) was induced in C57BL/6 mice by injecting anti-CII antibodies. Mice received 10 μg/g of TFM-C or celecoxib every other day. The effects of TFM-C on clinical and histopathological severities were assessed. The serum levels of CII-specific antibodies were measured by ELISA. The effects of TFM-C on mast cell activation, cytokine producing capacity by macophages, and neutrophil recruitment were also evaluated.

Results

TFM-C inhibited the severity of CIA and CAIA more strongly than celecoxib. TFM-C treatments had little effect on CII-specific antibody levels in serum. TFM-C suppressed the activation of mast cells in arthritic joints. TFM-C also suppressed the production of inflammatory cytokines by macrophages and leukocyte influx in thioglycollate-induced peritonitis.

Conclusion

These results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis.