TGF-β type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody
TGF-β type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody
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DOI：
10.1093/intimm/dxl128
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Nakao, Atsuhito
中科院分区：
文献类型：
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作者：
Sakuma, Michitomo;Hatsushika, Kyosuke;Nakao, Atsuhito
风湿性关节炎（RA）的特征在于肥大的滑膜组织，其包括过度增殖的滑膜成纤维细胞和浸润的炎性细胞。转化生长因子-β（TGF-β）是一种多功能细胞因子，通过作用于各种细胞类型来调节细胞生长、炎症和血管生成。在RA滑膜组织中，TGF-β以高水平表达。然而，TGF-β在RA中的确切作用仍不清楚。我们在此证明了TGF-β诱导的RA滑膜细胞增殖和血小板衍生生长因子（PDGF）-AA诱导之间的因果关系。此外，TGF-β诱导RA滑膜成纤维细胞产生IL-6和血管内皮生长因子（VEGF），与核因子-κ B活化相关。TGF-β对RA滑膜成纤维细胞的这些作用被TGF-β I型受体激酶抑制剂HTS 466284抑制。此外，根据临床表现、组织学、肿瘤坏死因子-α、PDGF和VEGF表达以及5-溴-2 '-脱氧尿苷掺入，HTS 466284显著预防抗II型胶原抗体诱导的小鼠关节炎。这些体外和体内结果表明，TGF-β在由滑膜细胞增殖、炎症和血管生成组成的滑膜增生的发展中发挥作用。因此，阻断TGF-β信号传导可能成为治疗RA的另一种策略。
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.