Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid
Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid
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DOI：
10.1038/sj.bjp.0704955
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发表时间：
2002-12-01
影响因子：
7.3
通讯作者：
Lin, WW
中科院分区：
文献类型：
--
作者：
Chen, CW;Chao, Y;Lin, WW
1诱导型一氧化氮（Inducible nitric oxide，iNOS）被认为参与机体防御和炎症部位的组织损伤。在以往的研究中，我们发现核酸内切酶抑制剂金精三羧酸（ATA）对细菌脂多糖诱导的巨噬细胞死亡具有保护作用。这种作用是通过中断NF-κ B和AP-1激活的信号通路，从而中断iNOS表达。在这项研究中，我们已经解决了ATA对JAK-STAT信号通路的影响。2在小鼠RAW 264.7巨噬细胞中，IFN-γ介导的NO产生和iNOS表达通过3 - 100 μ mATA的存在浓度依赖性地降低。3 IFN-γ诱导的STAT 1活化，如从其酪氨酸磷酸化，核转位，与特异性DNA反应元件的结合和诱发的IRF-I报告基因测定，同时被ATA抑制，然而ATA不改变IFN-γ与RAW 264.7细胞的结合。4 JAK 1和JAK 2的活性，应答IFN-γ的STAT 1信号传导所必需的上游激酶也被ATA降低。5此外，IL-4、IL-10、GM-CSF和M-CSF引起STAT 3的酪氨酸磷酸化，巨噬细胞中的STAT 5和/或STAT 6因ATA的存在而减少。6综上所述，我们得出结论，ATA可以干扰JAK-STAT信号通路以响应细胞因子。这种作用有助于抑制IFN-γ诱导的iNOS表达。
1 Inducible nitric oxide (iNOS) is thought to involve in host defence and tissue damage in inflammatory loci. In previous study, we have found that the endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from cell death induced by bacterial lipopolysaccharide. This action is through the interruption with signalling pathways for NF-kappaB and AP-1 activation, and thus iNOS expression. In this study we have addressed the effects of ATA on JAK-STAT signalling pathways.2 In murine RAW 264.7 macrophages, IFN-gamma-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3 - 100 mum ATA.3 IFN-gamma-induced STAT1 activation, as assessed from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA response element and evoked IRF-I reporter gene assay, were concomitantly inhibited by ATA, However, ATA did not alter IFN-gamma binding to RAW 264.7 cells.4 The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signalling in response to IFN-gamma, were also reduced by ATA.5 Moreover, IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5 and/or STAT6 in macrophages were diminished by the presence of ATA.6 Taken together, we conclude that ATA can interfere JAK-STAT signalling pathways in response to cytokines. This action contributes to the inhibition of IFN-gamma-induced iNOS expression.