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首页> 外文期刊>Infection and immunity >Protein Kinase A-Mediated Inhibition of Gamma Interferon-Induced Tyrosine Phosphorylation of Janus Kinases and Latent Cytoplasmic Transcription Factors in Human Monocytes by Ehrlichia chaffeensis
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Protein Kinase A-Mediated Inhibition of Gamma Interferon-Induced Tyrosine Phosphorylation of Janus Kinases and Latent Cytoplasmic Transcription Factors in Human Monocytes by Ehrlichia chaffeensis

机译：蛋白质激酶A介导的恰菲尔埃里希氏体抑制γ干扰素诱导的人单核细胞Janus激酶酪氨酸磷酸化和细胞质潜在转录因子的酪氨酸磷酸化。

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Ehrlichia chaffeensis, an obligatory intracellular bacterium of monocytes or macrophages, is the etiologic agent of human monocytic ehrlichiosis. Our previous study showed that gamma interferon (IFN-γ) added prior to or at early stage of infection inhibited infection of human monocytes with E. chaffeensis; however, after 24 h of infection, IFN-γ had no antiehrlichial effect. To test whether ehrlichial infection disrupts Janus kinase (Jak) and signal transducer and activator of transcription (Stat) signaling induced by IFN-γ, tyrosine phosphorylation of Stat1, Jak1, and Jak2 in E. chaffeensis-infected THP-1 cells was examined by immunoprecipitation followed by immunoblot analysis. Viable E. chaffeensis organisms blocked tyrosine phosphorylation of Stat1, Jak1, and Jak2 in response to IFN-γ within 30 min of infection. Similar results were obtained with human peripheral blood monocytes infected with E. chaffeensis. Heat or proteinase K treatment but not periodate treatment of E. chaffeensisabrogated the inhibitory effect, suggesting that protein factor(s) ofE. chaffeensis is responsible for the inhibition of IFN-γ-induced tyrosine phosphorylation. Preincubation ofE. chaffeensis with the Fab fragment of dog anti-E. chaffeensis immunoglobulin G also abrogated the inhibitory effect. On the other hand, monodansylcadaverine, which does not block binding but blocks internalization of ehrlichiae into macrophages, did not have any influence on the tyrosine phosphorylation. These results indicate that ehrlichial binding to host cells is sufficient to inhibit Stat1 tyrosine phosphorylation induced by IFN-γ. Protein kinase A (PKA) activity in THP-1 cells increased approximately 25-fold within 30 min of infection with E. chaffeensis. In THP-1 cells pretreated with a PKA inhibitor, Rp isomer of adenosine 3′,5′-cyclic phosphorothioate, E. chaffeensis-induced inhibition of Stat1 tyrosine phosphorylation was partially abrogated. These results suggest thatE. chaffeensis blocks IFN-γ-induced tyrosine phosphorylation of Jak and Stat through raising PKA activity in THP-1 cells, which may be an important survival mechanism of ehrlichiae within the host cell.
机译：单核细胞或巨噬细胞的必不可少的胞内细菌<埃菲尔希里氏菌是人类单核细胞埃希氏菌病的病原体。我们先前的研究表明，在感染之前或感染初期添加γ-干扰素（IFN-γ）可以抑制人单核细胞感染 E。 Chaffeensis ;但是，在感染后24小时，IFN-γ没有抗乙醛酸作用。为了测试埃希氏菌感染是否破坏Janus激酶（Jak）以及由IFN-γ诱导的信号转导和转录激活子（Stat）信号传导，在em中将Stat1，Jak1和Jak2的酪氨酸磷酸化。通过免疫沉淀法和免疫印迹分析法检测了恰菲菌属感染的THP-1细胞。可行的 E。 Chaffeensis 生物在感染后30分钟内阻断Stat1，Jak1和Jak2的酪氨酸磷酸化。用 E感染的人外周血单核细胞获得了相似的结果。 chaffeensis 。加热或蛋白酶K处理，但不定期治疗E。 chaffeensis 具有抑制作用，提示 E的蛋白质因子。 chaffeensis 负责抑制IFN-γ诱导的酪氨酸磷酸化。 E.E的预孵育。 chaffeensis ，带有狗抗 E的Fab片段。 Chaffeensis 免疫球蛋白G也取消了抑制作用。另一方面，单丹磺酰尸胺不阻止结合，但阻止埃希氏菌内化成巨噬细胞，对酪氨酸磷酸化没有任何影响。这些结果表明，与宿主细胞的乙二醛结合足以抑制由IFN-γ诱导的Stat1酪氨酸磷酸化。在感染 E 30分钟内，THP-1细胞中的蛋白激酶A（PKA）活性增加了约25倍。 chaffeensis 。在用PKA抑制剂预处理的THP-1细胞中，腺苷3'，5'-环硫代磷酸酯 E的Rp异构体。 Chaffeensis 对Stat1酪氨酸磷酸化的抑制作用被部分废除。这些结果表明 E。 chaffeensis 通过提高THP-1细胞中的PKA活性来阻断IFN-γ诱导的Jak和Stat酪氨酸磷酸化，这可能是大肠杆菌在宿主细胞中的重要生存机制。

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