Roxithromycin Specifically Inhibits Development of Collagen Induced Arthritis and Production of Proinflammatory Cytokines by Human T Cells and Macrophages

YASUYO URASAKI, MAMORU NORI, SATOSHI IWATA, TAKAHIRO SASAKI, OSAMU HOSONO, HIROSHI KAWASAKI, HIROTOSHI TANAKA, NAM H. DANG, EIJI IKEDA, and CHIKAO MORIMOTO

ABSTRACT.

Objective. Roxithromycin (RXM) is a macrolide antibiotic that is effective in treatment of chronic lower respiratory tract diseases including diffuse panbronchiolitis and bronchial asthma. Its mechanism of action apart from its antibacterial action remains unclear. To determine the mechanism of action of RXM, we evaluated the effect of RXM on T cell functions and the inflammatory responses in mice with collagen induced arthritis (CIA).

Methods. T cell proliferation, cytokine production by T cells stimulated through CD28, CD26, or PMA with or without anti-CD3 Mab, cytokine production by macrophages stimulated with lipopolysaccharide, and transendothelial migration of T cells were analyzed in the presence or absence of various concentrations of RXM. We evaluated the effect of RXM treatment in collagen induced arthritis in mice.

Results. RXM did not affect the production of Th1-type and Th2-type cytokines, whereas it specifically inhibited production of proinflammatory cytokines such as tumor necrosis factor-a and interleukin 6 (IL-6) by T cells and macrophages. RXM inhibited T cell migration. We found that RXM treatment of mice with CIA reduced the severity of arthritis and serum level of IL-6, as well as leukocyte migration into the affected joints and destruction of bones and cartilage.

Conclusion. Our findings strongly suggest that RXM may be useful for the therapy of rheumatoid arthritis as well as other inflammatory diseases such as Crohn's disease. (J Rheumatol 2005; 32:1765–74)

Key Indexing Terms:

ROXITHROMYCIN
PROINFLAMMATORY CYTOKINE
T CELLS
COSTIMULATION
COLLAGEN INDUCED ARTHRITIS
MACROPHAGES
RHEUMATOID ARTHRITIS

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From the Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo; Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, Texas, USA; and Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

Supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan.

Y. Urasaki, MS; M. Nori, MD; S. Iwata, MD; T. Sasaki, MD; O. Hosono, MD; H. Kawasaki, MD; H. Tanaka, MD, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo; N.H. Dang, MD, M.D. Anderson Cancer Center; E. Ikeda, MD, Department of Pathology, Keio University School of Medicine; C. Morimoto, MD, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo.

Address reprint requests to Dr. C. Morimoto, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 Japan. E-mail: morimoto@ims.u-tokyo.ac.jp

Accepted for publication April 1, 2005.

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