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International Immunology Advance Access originally published online on November 29, 2006
International Immunology 2007 19(2):117-126; doi:10.1093/intimm/dxl128
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

TGF-ß type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody

Michitomo Sakuma1,2, Kyosuke Hatsushika1, Kensuke Koyama1, Ryohei Katoh3, Takashi Ando1, Yoshiyuki Watanabe1, Masanori Wako1, Mirei Kanzaki1, Shinichi Takano1, Hajime Sugiyama2, Yoshiki Hamada2, Hideoki Ogawa4, Ko Okumura4 and Atsuhito Nakao1,4

1 Department of Immunology
2 Department of Orthopaedic Surgery
3 Department of Human Pathology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
4 Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan

Correspondence to: A. Nakao; E-mail: anakao{at}yamanashi.ac.jp

Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-ß is expressed at high levels. However, the precise role of TGF-ß in RA remains unclear. We herein demonstrated a causal link between the TGF-ß-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-ß induced IL-6 and vascular endothelial growth factor (VEGF) production by RA synovial fibroblasts associated with nuclear factor-kappa B activation. These effects of TGF-ß on RA synovial fibroblasts were suppressed by TGF-ß type I receptor kinase inhibitor HTS466284. Furthermore, HTS466284 significantly prevented anti-collagen type II antibody-induced arthritis in mice according to the clinical manifestations, histology, tumor necrosis factor-{alpha}, PDGF and VEGF expression and 5-bromo-2'-deoxyuridine incorporation. These in vitro and in vivo results suggest that TGF-ß plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-ß signaling may thus become an additional strategy for the treatment of RA.

Keywords: rheumatoid arthritis

Transmitting editor: H. Karasuyama


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