Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Celecoxib Analogue Lacking COX-2-Inhibitory Activity Inhibits Arthritis by Supressing IL-23 and Inflammatory Cytokines.

Chiba2,  Asako, Tajima2,  Ryohsuke, Mizuno2,  Miho, Tomi2,  Chiharu, Alloza3,  Iraide, Yamamura2,  Takashi, Vandenbroeck3,  Koen

Department of Immunology, National Institute of Neuroscience, NCNP, Kodaira Tokyo, Japan
Department of Immunology, National Institute of Neuroscience, NCNP
Neurogenomiks Laboratory, Ikerbasque and Universidad Del País Vasco (UPV/EHU), Parque Tecnológico de Bizkaia

Background:

Previously we reported that a trifluoromethyl analogue of celecoxib (TFM-celecoxib) lacking COX-2-inhibitory activity induces cellular retention of IL-12 and IL-23. Because these cytokines are involved in autoimmune or inflammatory diseases, we asked whether TFM-celecoxib suppresses animal models of arthritis.

Methods:

To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) (150mg) in Freund's complete adjuvant containing 250mg of H37Ra Mycobacterium tuberculosis on day 0 and CII in IFA on day 21. Antibody-induced arthritis (AIA) was induced in C57BL/6 mice by injecting a mixture of anti-CII antibodies followed by lipopolysaccharide (LPS) administration 2 days later. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunizing with MOG35–55-peptide (100mg) in CFA followed by pertussis toxin administration. Peritoneal recruitment of leukocytes was induced by injecting 1ml of 4% thioglycollate. Mice recieved 10mg/kg of TFM-celecoxib (TFM-C) every other day from day 1 in EAE and AIA experiments, every day from day 21 in CIA experiments. The control animals were injected with vehicle alone, and in some experiments another group of mice were treated with celecoxib. Bone marrow-derived dendritic cells (BMDCs) or splenic macrophages from mice treated with TFM-C were stimulated by LPS in vitro in the presense or absence of TFM-C, and cytokine consentration in the culture supernatants was measured by ELISA

Results:

TFM-C strongly suppressed CIA and AIA, although celecoxib did not inhibit these models. Histopathological analysis of arthritic joints revealed that TFM-C treatment inhibited mast cell degranulation whereas celecoxib treatment failed to suppress mast cell activation. TFM-C suppressed mast cell-dependent neutrophil influx into peritoneal cavity after injection of thioglycollate. TFM-C treatment in vivo inhibited inflammatory cytokines production from macrophages. Moreover, TFM-C suppressed the clinical and pathological features of EAE in association with the reduction of IL-23 production by dendritic cells, which subsequently suppressed IL-17 production by lymph node cells when re-challenged by MOG in vitro.

Conclusion:

TFM-C suppressed murine models of arthritis by suppressing innate immune cell activation and autoreactive T cell responses, highlighting the therapeutic potential of TFM-C for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

To cite this abstract, please use the following information:
Chiba, Asako, Tajima, Ryohsuke, Mizuno, Miho, Tomi, Chiharu, Alloza, Iraide, Yamamura, Takashi, et al; Celecoxib Analogue Lacking COX-2-Inhibitory Activity Inhibits Arthritis by Supressing IL-23 and Inflammatory Cytokines. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :896
DOI: 10.1002/art.28664

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