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首页> 外文期刊>Infection and immunity >The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection
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The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

机译：人类P-糖蛋白转运蛋白增强对单核细胞增生李斯特菌感染的I型干扰素反应

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摘要

Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted by L. monocytogenes during infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restricted L. monocytogenes or lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P-gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps.
机译：人多药外排转运蛋白以其将抗生素和有毒化合物从细胞中挤出的能力而著称，但积累的数据表明它们在与药外排无关的多种生理过程中具有其他功能。在这里，我们显示人类多药转运蛋白P-糖蛋白（P-gp）（也称为MDR1和ABCB1）在感染人类细胞内细菌病原体单核细胞增生性李斯特菌后，在单核细胞系THP-1中被转录诱导。值得注意的是，我们发现P-gp对于完全激活针对单核细胞增生李斯特氏菌的I型干扰素反应非常重要。维拉帕米抑制P-gp功能和使用mRNA沉默抑制其转录均导致感染细胞中I型反应的幅度降低。 P-gp的这种功能特定于针对细胞质复制细菌引起的I型干扰素细胞因子，未观察到对环二安培（c-di-AMP）的反应，环二安培（c-di-AMP）被证明是由单核细胞增生李斯特菌分泌的。感染并触发I型干扰素。此外，P-gp不参与其他促炎细胞因子的激活，例如由液泡限制性单核细胞增生李斯特氏菌或脂多糖（LPS）触发的那些。综上所述，这些发现证明了P-gp在针对细胞内病原体的固有免疫应答的适当发育中的作用，突显了采用包括抑制多药耐药性（MDR）外排泵的治疗策略的复杂性。

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