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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/G1392    most recent 00599.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Siccardi, D. Articles by McCormick, B. A. PubMed PubMed Citation Articles by Siccardi, D. Articles by McCormick, B. A.

INFLAMMATION/IMMUNITY/MEDIATORS

Salmonella enterica serovar Typhimurium modulates P-glycoprotein in the intestinal epithelium

Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts and the Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts

Submitted 21 December 2007 ; accepted in final form 6 April 2008

Studies over the last decade have shown that Salmonella enterica serovar Typhimurium (S. typhimurium) is able to preferentially locate to sites of tumor growth and modulate (shrink) the growth of many cancers. Given this unique association between S. typhimurium and cancer cells, the objective of this study was to investigate the capacity of this microorganism to modulate the plasma membrane multidrug resistance (MDR) protein P-glycoprotein (P-gp), an ATP-binding cassette transporter responsible for effluxing many cancer drugs. Using an in vitro model of S. typhimurium infection of polarized human cancer intestinal cell lines, we have found that this enteric pathogen functionally downregulates the efflux capabilities of P-gp. Specifically, we show that S. typhimurium infection of human intestinal cancer cells results in the enhanced intracellular accumulation of a number of P-gp substrates that corresponds to the posttranscriptional downregulation of P-gp expression. Furthermore, cells expressing small interfering RNAs against MDR1, the gene encoding P-gp, were significantly more susceptible to the cytotoxic effects of bacterial infection. This result is consistent with our observation that S. typhimurium was significantly less able to invade cells overexpressing MDR1. Taken together, these results reveal a novel role for P-gp in the maintenance of homeostasis in the gastrointestinal tract in regard to bacterial infection. Thus the regulation of P-gp by S. typhimurium has important implications not only for the development of new cancer therapeutics aimed at reversing drug resistance but also in the understanding of how microbes have evolved diverse strategies to interact with their host.

ATP-binding cassette transporter; inflammation; multidrug resistance 1