Rheumatology Advance Access published online on February 29, 2008
Rheumatology, doi:10.1093/rheumatology/ken006
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Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA
1Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, 2Department of Joint Disease and Rheumatism, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 and 3Department of Orthopaedic Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Correspondence to:
S. Kamijo, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: s-kamijo{at}med.juntendo.ac.jp
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Abstract |
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Objective. TWEAK, TNF-like weak inducer of apoptosis, induces not only apoptosis of some tumour cells, but also proliferation of endothelial cells, and angiogenesis. It is known that TWEAK induces production of cytokines that are involved in the pathogenesis of RA. However, it is not clear how TWEAK takes part in the synovitis of RA. In this study, we investigated the role of TWEAK/fibroblast growth factor-inducible 14 (Fn14) interaction in the synovitis of RA.
Methods. TWEAK and Fn14 expression on RA and OA synovial cells (SCs) were analysed by FACS. Synovial fibroblasts (SFs) or freshly isolated SCs were cultured in the presence or absence of recombinant TWEAK (rTWEAK) and anti-TWEAK or anti-Fn14 mAbs. Cell proliferation, cytokine/chemokine production and intercellular adhesion molecule (ICAM-1) expression were measured by WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt], ELISA and FACS, respectively.
Results. TWEAK expression was detected on CD45-positive population in RA synovium, whereas Fn14 was detected on both CD45-positive and CD45-negative populations. Cultured RA and OA SFs showed higher proliferation and produced IL-6, IL-8 and MCP-1 in response to rTWEAK. Cell proliferation and cytokine production of freshly isolated SCs from RA patients were suppressed by anti-TWEAK and anti-Fn14 mAbs. ICAM-1 expression on RA, but not OA, SFs was up-regulated by rTWEAK.
Conclusions. These data suggest that TWEAK/Fn14 interaction plays a substantial role in the synovitis of RA, by directly inducing the proliferation of SFs, and by up-regulating the production of inflammatory cytokines/chemokines as well as the expression of ICAM-1.
KEY WORDS: Rheumatoid arthritis, Cytokines, Chemokines, Adhesion molecules
Submitted 10 November 2006;
revised version accepted 4 January 2008.
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