Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis
Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis
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DOI：
10.1172/jci28546
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发表时间：
2006-10-01
影响因子：
15.9
通讯作者：
Robinson, William H.
中科院分区：
文献类型：
--
作者：
Paniagua, Ricardo T.;Sharpe, Orr;Robinson, William H.
酪氨酸激酶在信号转导通路和细胞反应的激活中起核心作用，介导类风湿关节炎的发病机制。甲磺酸伊马替尼（Imatinib甲磺酸伊马替尼）是一种酪氨酸激酶抑制剂，用于治疗表达Bcr/ abl的白血病，随后发现用于治疗表达c- kit的胃肠道间质瘤。我们证明伊马替尼有效地预防和治疗小鼠胶原诱导关节炎（CIA）。我们进一步表明，微摩尔浓度的伊马替尼可以阻断与RA发病有关的多种信号转导途径，包括肥大细胞c-Kit信号传导和tnf - α释放，巨噬细胞c-Fms激活和细胞因子产生，成纤维细胞PDGFR信号传导和增殖。在我们的研究中，伊马替尼减弱了人类RA患者的成纤维细胞样滑膜细胞（FLSs）中的PDGFR信号和滑膜液单个核细胞（SFMCs）中tnf - α的产生。伊马替尼介导的一系列信号转导通路和下游致病细胞反应的抑制可能为治疗类风湿性关节炎和其他炎症性疾病提供了一种强有力的方法。
Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.