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Production and Contribute to the Exacerbation of Inflammatory Arthritis1
* Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and
Department of Transfusion Medicine and Immunohematology, University of Tokyo, Tokyo, Japan
IL-17A is a T cell-derived proinflammatory cytokine that contributes to the pathogenesis of rheumatoid arthritis. Recently, six related molecules have been identified to form the IL-17 family, as follows: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Whereas IL-17A and IL-17F up-regulate IL-6 in synovial fibroblasts, IL-17B and IL-17C are reported to stimulate the release of TNF-
and IL-1β from the monocytic cell line, THP-1 cell. However, their detailed function remains to be elucidated. We report in this study the effects of IL-17 family on the collagen-induced arthritis (CIA) progression by T cell gene transfer and bone marrow chimeric mice. The mRNA expressions of IL-17 family (IL-17A, IL-17B, IL-17C, and IL-17F) and their receptor (IL-17R and IL-17Rh1) genes in the arthritic paws of CIA mice were elevated compared with controls. Although IL-17A and IL-17F were expressed in CD4+ T cells, IL-17B and IL-17C were expressed in the cartilage and in various cell populations in the CIA arthritic paws, respectively. In vitro, IL-17A, IL-17B, IL-17C, and IL-17F induced TNF- production in mouse peritoneal exudate cells. In vivo, adoptive transfer of IL-17B- and IL-17C-transduced CD4+ T cells evidently exacerbated arthritis. Bone marrow chimeric mice of IL-17B and IL-17C exhibited elevated serum TNF- concentration and the high arthritis score upon CIA induction. Moreover, neutralization of IL-17B significantly suppressed the progression of arthritis and bone destruction in CIA mice. Therefore, not only IL-17A, but also IL-17B and IL-17C play an important role in the pathogenesis of inflammatory arthritis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Program and Project Grant funding from Japan Society for the Promotion of Science; Ministry of Health, Labour and Welfare; and Ministry of Education, Culture, Sports, Science and Technology.
2 Address correspondence and reprint requests to Dr. Keishi Fujio, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. E-mail address: kfujio-tky{at}umin.ac.jp
3 Abbreviations used in this paper: RA, rheumatoid arthritis; BCII, bovine type II collagen; BM, bone marrow; CIA, collagen-induced arthritis; mIL, murine IL; MMP, matrix metalloproteinase; PEC, peritoneal exudate cell; pMIG, murine stem cell virus/internal ribosome entry site/GFP.
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