The RD1 Locus in the Mycobacterium tuberculosis Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages
The RD1 Locus in the Mycobacterium tuberculosis Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages
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DOI：
10.1128/iai.00015-09
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发表时间：
2009-09-01
影响因子：
3.1
通讯作者：
Mitsuyama, Masao
中科院分区：
文献类型：
--
作者：
Kurenuma, Takeshi;Kawamura, Ikuo;Mitsuyama, Masao
结核分枝杆菌中一个被称为“差异区1”（RD 1）的基因组位点已被证明有助于宿主保护性免疫的产生以及细菌的毒力。为了深入了解分子机制，我们研究了H37 Rv和RD 1缺陷突变株（Delta RD 1）之间的精氨酸诱导能力的差异。我们发现RD 1与受感染的巨噬细胞产生半胱天冬酶-1依赖性细胞因子白细胞介素-18（IL-18）和IL-1 β有关。这些细胞因子的表达在感染H37 Rv和Delta RD 1后类似地被诱导。然而，caspase-1的激活仅在H37 Rv感染的巨噬细胞中观察到。细胞因子的产生和半胱天冬酶-1的激活诱导独立的I型干扰素受体信号转导事件。我们还发现，caspase-1的激活显着抑制细胞外KCl浓度的增加。此外，IL-18和IL-1 β的产生以及半胱天冬酶-1的活化独立于P2 X7嘌呤能受体被诱导，并且Delta RD 1在半胱天冬酶-1活化中的无能被尼日利亚菌素（一种诱导钾离子流出的试剂）补偿。基于这些结果，我们得出结论，RD 1通过诱导感染的巨噬细胞中的钾离子流出参与caspase-1依赖性细胞因子的产生。
A genomic locus called "region of difference 1" (RD1) in Mycobacterium tuberculosis has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 (Delta RD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1 beta, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and Delta RD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1 beta and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of Delta RD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages.