Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis
Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis
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DOI：
10.1007/s10165-010-0392-5
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发表时间：
2011-06-01
影响因子：
2.2
通讯作者：
Sumida, Takayuki
中科院分区：
文献类型：
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作者：
Akashi, Naotsugu;Matsumoto, Isao;Sumida, Takayuki
伊马替尼和尼洛替尼是选择性靶向一系列蛋白酪氨酸激酶的抑制剂，包括Abelson激酶(Abl)、嵌合癌蛋白、断点簇区Abelson激酶(BCR-Abl)以及干细胞因子受体(KIT)、血小板衍生生长因子受体(PDGFR)、盘状结构域受体(DDR)和集落刺激因子-1受体(CSF-1R)。本研究的目的是观察伊马替尼或尼洛替尼对葡萄糖-6-磷酸异构酶(GPI)诱导的小鼠关节炎的治疗作用。分别于不同时间点给予伊马替尼或尼洛替尼灌胃。通过视觉评分和测定抗GPI抗体的产生来评价疗效。用GPI分别与伊马替尼和尼洛替尼共同培养关节炎小鼠的脾细胞，分析培养上清液中细胞因子的水平。为探讨伊马替尼和尼洛替尼对T细胞增殖的影响，采用体外培养的方法，将关节炎小鼠的淋巴结细胞与GPI共同培养。采用实时定量聚合酶链式反应(RT-PCR)检测关节炎性关节组织中白介素17(IL-17)的表达。从第0天开始服用伊马替尼可显著抑制关节炎(P<；0.05)，从第0天开始服用尼洛替尼可显著抑制关节炎(P<；0.01)，从第7天开始服用尼洛替尼可显著抑制关节炎的进展(P<；0.05)。抗GPI抗体的降低与伊马替尼的疗效有关，但与尼洛替尼的疗效无关。伊马替尼可剂量依赖性地抑制脾细胞产生肿瘤坏死因子α、IL-6、干扰素和IL-17，而尼洛替尼仅以剂量依赖方式抑制IL-17和干扰素-γ的产生。3 mU M的伊马替尼对CD4+T细胞的增殖抑制作用较弱(P<0.05)，10 mU M的伊马替尼和3、10 mU M的尼洛替尼对CD4+T细胞的增殖抑制作用显著(P<0.01)。伊马替尼和尼洛替尼预防自身免疫性关节炎的作用机制不同，伊马替尼抑制炎症细胞因子和T细胞来源的细胞因子的产生，尼洛替尼抑制T细胞来源的细胞因子的产生。伊马替尼和尼洛替尼可能对类风湿性关节炎(RA)和其他炎症性疾病具有治疗潜力。
Imatinib and nilotinib are inhibitors that selectively target a set of protein tyrosine kinases, including abelson kinase (Abl), together with the chimeric oncoprotein, breakpoint cluster region-abelson kinase (Bcr-Abl), as well as stem cell factor receptor (KIT), platelet-derived growth factor receptor (PDGFR), discoidin domain receptor (DDR), and colony stimulating factor-1 receptor (CSF-1R). The aim of the present study was to investigate whether imatinib or nilotinib was effective against arthritis in the glucose-6-phosphate isomerase (GPI)-induced arthritis mouse model. Imatinib or nilotinib was administered orally to the arthritic mice at different time points. Efficacy was evaluated by visual scoring and by determining the production of anti-GPI antibody. Splenocytes from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro, and cytokine levels in the culture supernatants were analyzed. To investigate the effects of imatinib and nilotinib on T-cell proliferation, lymph node cells from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro. Interleukin (IL)-17 mRNA expression in the arthritic ankle joints from the onset of arthritis was analyzed by real-time polymerase chain reaction (PCR). The administration of imatinib from day 0 showed suppression of arthritis (P < 0.05), the administration of nilotinib from day 0 resulted in pronounced suppression of arthritis (P < 0.01), and that from day 7 showed significant inhibition of the progression of arthritis (P < 0.05). A reduction in anti-GPI antibodies was correlated with the therapeutic efficacy of imatinib, but not with that of nilotinib. Imatinib dose-dependently inhibited tumor necrosis factor (TNF)-alpha, IL-6, interferon (IFN)-gamma, and IL-17 production by splenocytes in vitro, while nilotinib inhibited only IL-17 and IFN-gamma production in a dose-dependent fashion. Imatinib at 3 mu M exerted a mild antiproliferative effect on CD4+ T cells (P < 0.05), whereas imatinib at 10 mu M and nilotinib at 3 and 10 mu M demonstrated a marked antiproliferative effect (P < 0.01). The IL17 gene expression level on day 7 tended to be higher than that on day 14. These findings suggest that imatinib and nilotinib could prevent autoimmune arthritis, essentially via distinct mechanisms, in that imatinib inhibits both inflammatory and T-cell-derived cytokine production, whereas nilotinib suppresses T-cell-derived cytokine production. Imatinib and nilotinib could have therapeutic potential for rheumatoid arthritis (RA) and other inflammatory diseases.