title: The human P-glycoprotein transporter enhances the type I interferon response to Listeria monocytogenes infection.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Sigal
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Millie
authors.initials: M
authors.lastname: Kaplan Zeevi
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, and Department of Material Science and Engineering, Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Weinstein
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, and Department of Material Science and Engineering, Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel anathe@post.tau.ac.il.
authors.forename: Anat A
authors.initials: AA
authors.lastname: Herskovits
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta; D008089:Listeria monocytogenes / Q000502:physiology*; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D014700:Verapamil / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007370:Interferon Type I; D016899:Interferon-beta; D014700:Verapamil
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