CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes.
CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes.
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CP690,550抑制了类风湿滑膜细胞中的OnCostatin M诱导的JAK/Stat信号通路。
DOI：
10.1186/ar3333
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发表时间：
2011-05-06
影响因子：
4.9
通讯作者：
Ishibashi H
中科院分区：
文献类型：
--
作者：
Migita K;Komori A;Torigoshi T;Maeda Y;Izumi Y;Jiuchi Y;Miyashita T;Nakamura M;Motokawa S;Ishibashi H
白介素6型细胞因子通过激活Janus激酶/信号转导和转录激活因子(JAK/STAT)信号通路发挥作用。JAK/STAT通路在类风湿性关节炎中起着重要作用，因为JAK抑制剂在临床试验中对类风湿性关节炎(RA)有显著的疗效。在这项研究中，我们研究了小分子JAK抑制剂CP690,550对JAK/STAT信号通路的分子作用，并探讨了JAK激酶在类风湿滑膜炎中的作用。分离类风湿关节炎(RA)患者滑膜成纤维细胞(FLS)，用重组人抑瘤素M(OSM)刺激。用细胞因子蛋白芯片分析细胞上清液。采用实时荧光定量聚合酶链式反应(Real-time PCR)和酶联免疫吸附试验(ELISA法)检测IL-6mRNA和蛋白表达。用磷酸化特异性抗体用Western印迹法检测类风湿滑膜细胞的蛋白磷酸化。OSM对FLS中IL-6有较强的诱导作用。OSM刺激引起STATS的快速磷酸化，提示FLS中JAK/STAT通路被激活。CP690,550可完全阻断OSM诱导的IL-6的产生，以及OSM诱导的JAK/STAT和FLS中丝裂原活化蛋白激酶(MAPK)的激活。这些发现提示IL-6型细胞因子通过激活类风湿滑膜细胞中的JAK/STAT通路参与类风湿滑膜炎的发病。CP690,550对这些促炎信号通路的抑制在RA的治疗中可能是重要的。
Interleukin (IL)-6-type cytokines exert their effects through activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade. The JAK/STAT pathways play an important role in rheumatoid arthritis, since JAK inhibitors have exhibited dramatic effects on rheumatoid arthritis (RA) in clinical trials. In this study, we investigated the molecular effects of a small molecule JAK inhibitor, CP690,550 on the JAK/STAT signaling pathways and examined the role of JAK kinases in rheumatoid synovitis. Fibroblast-like synoviocytes (FLS) were isolated from RA patients and stimulated with recombinant oncostatin M (OSM). The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA, respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies. OSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK/STAT pathway in FLS. CP690,550 pretreatment completely abrogated the OSM-induced production of IL-6, as well as OSM-induced JAK/STAT, and activation of mitogen-activated kinases (MAPKs) in FLS. These findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK/STAT pathway in rheumatoid synoviocytes. Inhibition of these pro-inflammatory signaling pathways by CP690,550 could be important in the treatment of RA.
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影响因子：
27.4
作者：
Walker, J. G.;Ahern, M. J.;Smith, M. D.
通讯作者：
Smith, M. D.
影响因子：
--
作者：
Kremer, Joel M.;Bloom, Bradley J.;Zwillich, Samuel H.
通讯作者：
Zwillich, Samuel H.
影响因子：
--
作者：
Lin, Tsung H.;Hegen, Martin;Seidl, Katherine J.
通讯作者：
Seidl, Katherine J.
影响因子：
13.6
作者：
Fonseca, J. E.;Santos, M. J.;Choy, E.
通讯作者：
Choy, E.
影响因子：
27.4
作者：
Hui, W;Bell, M;Carroll, G
通讯作者：
Carroll, G