The human P-glycoprotein transporter enhances the type I interferon response to Listeria monocytogenes infection

• Published in: Infection and immunity 2015-06, Vol.83 (6), p.2358-2368
• Main Authors: Sigal, Nadejda, Kaplan Zeevi, Millie, Weinstein, Shiri, Peer, Dan, Herskovits, Anat A
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Line; Cellular Microbiology: Pathogen-Host Cell Molecular Interactions; Gene Expression Regulation; Humans; Interferon Type I - genetics; Interferon Type I - metabolism; Interferon-beta; Listeria monocytogenes; Listeria monocytogenes - physiology; Macrophages; Mice; Mice, Knockout; Verapamil - pharmacology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00380-15

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.