The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

Abstract

bHuman 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. Multidrug transporters mediate the active efflux of a wide range of drugs and xenobiotics, including antibiotics and chemotherapeutics (1). This permissive efflux ability engenders multidrug resistance (MDR)-a phenomenon that largely underlies the failure of various chemotherapeutic treatments (2-4). Human MDR transporters harbor an ATP-binding cassette (ABC), which defines the ABC-type superfamily, comprising more than 45 proteins in the human genome (5). Among these, several transporters have been extensively studied, such as the P-glycoprotein (P-gp) (also named MDR1 and ABCB1) (6), BCRP (ABCG2) (7), and MRP1 (ABCC1) (8), which were all shown to exhibit clinically relevant MDR functions (9). P-gp, encoded by the MDR1 gene, is the most prominent and best-characterized member of the ABCtype superfamily, first isolated in clinical cancers (6, 10). Aside from its well-documented multidrug resistance function in cancer cells, P-gp is naturally expressed in a variety of normal tissues and cells, including immune cells, such as macrophages, dendritic cells, T and B lymphocytes, and natural killer (NK) cells, and was shown to possess physiological functions beyond detoxification (11-15). Several studies have indicated roles for P-gp in lipid transport, intracellular trafficking of cholesterol, cell death, cell differentiation, and immune responses (16,17). Regarding the last, P-gp was shown to exhibit immunomodulatory activity and to influence the secretion of various inflammatory mediators,...

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

“…Infection of the monocytic cell line THP-1with the bacterial pathogen Listeria monocytogenes transcriptionally induced Pgp, which activated a Type I IFNresponse against L. monocytogenes bacteria. Both, inhibition of Pgp function by verapamil, or inhibition of its transcription using mRNA silencing, led to a reduced Type I response (i.e., reduced IFN release) in infected cells (101).…”

P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers

“…But it remains unclear whether p-gp is capable of directly expelling virulence factors and toxins of bacterial pathogens from host cells. Signaling via p-gp might also fight infection by activating distinct immune processes, such as inducing production of type I interferon in response to Listeria monocytogenes [ 50 ].…”

Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers

“…Furthermore, inflammation-induced changes of transporters in immune cells are reported [ 47 , 63 ]. Upregulation of gene and protein expression and function of MDR1 were reported in human blood mononuclear cells after treatment with cytokines [ 64 ] and gene expression of MDR1 was upregulated in the monocytic cell line THP-1 after infection with Listeria monocytogenes [ 65 ]. We have only found two studies in mammary epithelial cells on drug transporters after treatment with cytokines and both reported up-regulation of transporters.…”