A 4-Trifluoromethyl Analogue of Celecoxib Inhibits Arthritis by Suppressing Innate Immune Cell Activation

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 mu g/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. TFMC 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.This work was supported by Japan Foundation for Neuroscience and Mental Health (AC), a Grant-in-Aid for Scientific Research (B: 7210 to SM) from the Japan Society for the Promotion of Science, and Health and Labour Sciences Research Grants on Intractable Diseases (Neuroimmunological Diseases) from the Minitry of Health, Labour and Welfare of Japan; and by grants to KV from the Ministerio de Ciencia e Innovacion, Madrid, Spain (MEC-2008; SAF2008-00433) and from the Gobierno Vasco's SAIOTEK Program (Ref. S-PE09UN33)