title: Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA.
abstract: 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.
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. s-kamijo@med.juntendo.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Kamijo
authors.forename: A
authors.initials: A
authors.lastname: Nakajima
authors.forename: K
authors.initials: K
authors.lastname: Kamata
authors.forename: H
authors.initials: H
authors.lastname: Kurosawa
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000074049:Cytokine TWEAK; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D018799:Intercellular Adhesion Molecule-1