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International Immunology Advance Access published online on November 29, 2006
International Immunology, 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
Received June 21, 2006
Accepted November 1, 2006

Article

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

Michitomo Sakuma 1, Kyosuke Hatsushika 2, Kensuke Koyama 2, Ryohei Katoh 3, Takashi Ando 2, Yoshiyuki Watanabe 2, Masanori Wako 2, Mirei Kanzaki 2, Shinichi Takano 2, Hajime Sugiyama 4, Yoshiki Hamada 4, Hideoki Ogawa 5, Ko Okumura 5, and Atsuhito Nakao 6 *

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

* To whom correspondence should be addressed.
Atsuhito Nakao, E-mail: anakao{at}yamanashi.ac.jp


  Abstract

Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-{beta} (TGF-{beta}) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-{beta} is expressed at high levels. However, the precise role of TGF-{beta} in RA remains unclear. We herein demonstrated a causal link between the TGF-{beta}-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-{beta} 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-{beta} on RA synovial fibroblasts were suppressed by TGF-{beta} 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-{beta} plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-{beta} signaling may thus become an additional strategy for the treatment of RA.

Keywords: rheumatoid arthritis.
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