Blockade of the PI-3K signalling pathway by the Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces macrophages to synthesize and secrete pro-inflammatory cytokines.
Blockade of the PI-3K signalling pathway by the Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces macrophages to synthesize and secrete pro-inflammatory cytokines.
复制标题
伴随放线菌聚集菌细胞致死膨胀毒素阻断 PI-3K 信号通路，诱导巨噬细胞合成和分泌促炎细胞因子。
DOI：
10.1111/cmi.12299
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发表时间：
2014
影响因子：
3.4
通讯作者：
Boesze-Battaglia,Kathleen
中科院分区：
文献类型：
--
作者：
Shenker,BruceJ;Walker,LisaP;Zekavat,Ali;Dlakić,Mensur;Boesze-Battaglia,Kathleen
放线菌共生聚集体致死性膨胀毒素（Cdt）诱导淋巴细胞G2期阻滞和凋亡;这些毒性作用是由于活性亚基CdtB，其作为磷脂酰肌醇-3，4，5-三磷酸（PIP 3）磷酸酶发挥作用。我们现在扩展我们的调查，并证明Cdt是能够扰乱人类巨噬细胞的功能。发现THP-1和单核细胞衍生的巨噬细胞对Cdt诱导的细胞凋亡不敏感。尽管如此，该毒素能够与巨噬细胞结合并干扰PI-3 K信号传导，导致PIP 3水平降低以及Akt和GSK 3 β磷酸化降低;这些变化伴随着激酶活性的伴随变化。单核细胞和巨噬细胞暴露于Cdt导致促炎细胞因子产生，包括IL-1β、TNFα和IL-6的表达和释放增加。此外，在Cdt存在下用TLR-2、TLR-3或TLR-4激动剂处理细胞导致相对于单独的激动剂增强的促炎反应。GSK 3 β抑制剂阻断了Cdt诱导的促炎细胞因子反应，表明PI-3 K阻断的关键作用，同时降低了GSK 3 β磷酸化和增加了激酶活性。总的来说，这些研究为Cdt在介导产Cdt微生物引起的疾病发病机制中的毒力潜力提供了新的见解。
TheAggregatibactor actinomycetemcomitanscytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes; these toxic effects are due to the active subunit, CdtB, which functions as a phosphatidylinositol‐3,4,5‐triphosphate (PIP3) phosphatase. We now extend our investigation and demonstrate that Cdt is able to perturb human macrophage function. THP‐1‐ and monocyte‐derived macrophages were found not to be susceptible to Cdt‐induced apoptosis. Nonetheless, the toxin was capable of binding to macrophages and perturbing PI‐3K signalling resulting in decreased PIP3 levels and reduced phosphorylation of Akt and GSK3β; these changes were accompanied by concomitant alterations in kinase activity. Exposure of monocytes and macrophages to Cdt resulted in pro‐inflammatory cytokine production including increased expression and release of IL‐1β, TNFα and IL‐6. Furthermore, treatment of cells with either TLR‐2, ‐3 or ‐4 agonists in the presence of Cdt resulted in an augmented pro‐inflammatory response relative to agonist alone. GSK3β inhibitors blocked the Cdt‐induced pro‐inflammatory cytokine response suggesting a pivotal role for PI‐3K blockade, concomitant decrease in GSK3β phosphorylation and increased kinase activity. Collectively, these studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt‐producing organisms.