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

• Published in: International immunology 2007-02, Vol.19 (2), p.117-126
• Main Authors: Sakuma, Michitomo, Hatsushika, Kyosuke, Koyama, Kensuke, Katoh, Ryohei, Ando, Takashi, Watanabe, Yoshiyuki, Wako, Masanori, Kanzaki, Mirei, Takano, Shinichi, Sugiyama, Hajime, Hamada, Yoshiki, Ogawa, Hideoki, Okumura, Ko, Nakao, Atsuhito
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - metabolism; Arthritis, Experimental - prevention & control; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Collagen Type II - immunology; Down-Regulation; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Interleukin-6 - metabolism; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - drug effects; Mice; Mice, Inbred BALB C; Receptors, Transforming Growth Factor beta - drug effects; Receptors, Transforming Growth Factor beta - metabolism; Reverse Transcriptase Polymerase Chain Reaction; rheumatoid arthritis; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Vascular Endothelial Growth Factors - drug effects; Vascular Endothelial Growth Factors - metabolism
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxl128

Rheumatoid arthritis (RA) is characterized by hypertrophic synovial tissues comprising excessively proliferating synovial fibroblasts and infiltrating inflammatory cells. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell growth, inflammation and angiogenesis by acting on various cell types. In RA synovial tissues, TGF-β is expressed at high levels. However, the precise role of TGF-β in RA remains unclear. We herein demonstrated a causal link between the TGF-β-induced RA synovial cell proliferation and induction of platelet-derived growth factor (PDGF)-AA. In addition, TGF-β 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-β on RA synovial fibroblasts were suppressed by TGF-β 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-α, PDGF and VEGF expression and 5-bromo-2′-deoxyuridine incorporation. These in vitro and in vivo results suggest that TGF-β plays a role in the development of synovial hyperplasia consisting of synovial cell proliferation, inflammation and angiogenesis. The blockade of TGF-β signaling may thus become an additional strategy for the treatment of RA.