Isoniazid-induced control of Mycobacterium tuberculosis by primary human cells requires interleukin-1 receptor and tumor necrosis factor.
Isoniazid-induced control of Mycobacterium tuberculosis by primary human cells requires interleukin-1 receptor and tumor necrosis factor.
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异烟肼诱导的原代人类细胞对结核分枝杆菌的控制需要白介素 1 受体和肿瘤坏死因子。
DOI：
10.1002/eji.201646349
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发表时间：
2016
影响因子：
5.4
通讯作者：
Báfica,André
中科院分区：
文献类型：
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作者：
Yamashiro,LíviaH;Eto,Carolina;Soncini,Marina;Horewicz,Verônica;Garcia,Magno;Schlindwein,AlineD;Grisard,EdmundoC;Rovaris,DarcitaB;Báfica,André
促炎细胞因子是活动性结核病（ATB）中控制结核分枝杆菌（Mtb）生长的关键介质。为了进一步抑制患病个体中的细菌增殖，使用细胞壁合成的药物抑制剂如异烟肼（INH）。然而，INH是否在ATB期间通过调节宿主细胞因子对细菌生长产生间接影响尚不清楚。为了检验这一假设，我们使用了一种体外人类肉芽肿系统，该系统是由来自健康供体的原代白细胞生成的，适用于模型ATB。细胞培养物中Mtb的强烈增殖与单核细胞/巨噬细胞活化以及IL-1β和TNF的分泌相关。INH治疗显著降低了Mtb的存活率，但既不改变T细胞介导的Mtb杀伤，也不改变IL-1β和TNF的产生。然而，IL-1 R1和TNF信号传导的阻断挽救了INH诱导的杀伤，表明这些细胞因子在介导Mtb增殖控制中的协同作用。此外，INH杀死分枝杆菌高度依赖于病原体过氧化氢酶-过氧化物酶KatG的药物活化，并涉及宿主PI 3 K依赖性途径。最后，使用共感染（KatG突变株和H37 Rv株）细胞的实验表明，活性INH不会直接增强宿主介导的Mtb杀伤。因此，我们的研究结果表明，Mtb刺激的宿主IL-1和TNF在TB化疗中具有潜在的作用。
Proinflammatory cytokines are critical mediators that controlMycobacterium tuberculosis(Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) are employed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL‐1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T‐cell‐mediated Mtb killing, nor production of IL‐1β and TNF. However, blockade of both IL‐1R1 and TNF signaling rescued INH‐induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase‐peroxidase KatG and involved a host PI3K‐dependent pathway. Finally, experiments using coinfected (KatG‐mutated and H37Rv strains) cells suggested that active INH does not directly enhance host‐mediated killing of Mtb. Our results thus indicate that Mtb‐stimulated host IL‐1 and TNF have potential roles in TB chemotherapy.