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首页> 外文期刊>Infection and immunity >Attenuation of gamma interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1.
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Attenuation of gamma interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1.

机译：利什曼原虫感染的单核吞噬细胞中γ干扰素诱导的酪氨酸磷酸化的减弱：通过Janus激酶和Stat1选择性抑制信号传导。

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The induction of gene transcription in response to gamma interferon is impaired in mononuclear phagocytes infected with Leishmania donovani, and the mechanisms involved are not fully understood. The changes in gene expression brought about by gamma interferon are thought to involve transient increases in the activities of cellular protein tyrosine kinases, including the Janus kinases Jak1 and Jak2, leading to tyrosine phosphorylation of the transcription factor Stat1. To investigate the mechanisms accounting for the impaired responses to gamma interferon, a model system for examining overall changes in protein tyrosine phosphorylation, activation of Jak1 and Jak2 and phosphorylation of Stat1 was developed in phorbol 12-myristate 13-acetate-differentiated U-937 cells. Analysis of whole-cell lysates by antiphosphotyrosine immunoblotting showed that incubation with gamma interferon brought about specific increases in phosphotyrosine labeling of several proteins. Increased labeling of these proteins occurred to similar extents in control cells and in cells that had been infected with L. donovani for 16 h. Jak1, Jak2, and Stat1 were immunoprecipitated from control and interferon-treated cells, and tyrosine phosphorylation of these proteins, detected by antiphosphotyrosine immunoblotting was used to measured their activation. Tyrosine phosphorylation of Jak1, Jak2, and Stat1 increased markedly, in a dose-dependent manner, in U-937 cells incubated with gamma interferon. In contrast, in cells infected with L. donovani, tyrosine phosphorylation of Jak1, Jak2, and Stat1 was markedly impaired. This effect was dependent upon the duration of exposure to L. donovani and was maximal and complete at 16 h. Results similar to those observed with U-937 cells were also obtained with human peripheral blood monocytes. These findings indicate that infection of human mononuclear phagocytes with L. donovani leads to impaired gamma interferon-mediated tyrosine phosphorylation and selective effects on the Jak-Stat1 pathway. Unresponsiveness to gamma interferon for activation of this pathway may explain impaired transcriptional responses in leishmania-infected cells.
机译：在被多发利什曼原虫感染的单核吞噬细胞中，响应于γ-干扰素的基因转录诱导被削弱，并且所涉及的机制尚不完全清楚。 γ干扰素引起的基因表达变化被认为与细胞蛋白酪氨酸激酶（包括Janus激酶Jak1和Jak2）的活性瞬时增加有关，导致转录因子Stat1的酪氨酸磷酸化。为了研究对伽玛干扰素应答受损的机制，在佛波醇12-肉豆蔻酸酯13-乙酸酯分化的U-937细胞中开发了一个模型系统，用于检查蛋白质酪氨酸磷酸化，Jak1和Jak2的活化以及Stat1的磷酸化的总体变化。 。通过抗磷酸酪氨酸免疫印迹对全细胞裂解物进行的分析表明，与γ干扰素一起孵育会导致几种蛋白质的磷酸酪氨酸标记特异性增加。这些蛋白质的标记增加在对照细胞和已感染多诺氏乳杆菌16小时的细胞中以相似的程度发生。从对照和干扰素处理的细胞中免疫沉淀出Jak1，Jak2和Stat1，并通过抗磷酸酪氨酸免疫印迹检测这些蛋白质的酪氨酸磷酸化，以测量其活化。在与γ干扰素孵育的U-937细胞中，Jak1，Jak2和Stat1的酪氨酸磷酸化显着增加，呈剂量依赖性。相反，在感染了诺瓦氏乳杆菌的细胞中，Jak1，Jak2和Stat1的酪氨酸磷酸化明显受损。该效应取决于暴露于多诺氏乳杆菌的持续时间，并且在16 h达到最大和完全。用人外周血单核细胞也获得了与用U-937细胞观察到的结果相似的结果。这些发现表明，人诺瓦氏乳杆菌感染人单核吞噬细胞会导致γ干扰素介导的酪氨酸磷酸化受损，并对Jak-Stat1途径产生选择性影响。对γ干扰素激活该途径的无反应性可能解释了在利什曼原虫感染的细胞中转录反应受损。

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