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Mol. Biol. Cell 21 (4): 538-546

Copyright © 2010 by The American Society for Cell Biology.

Cell Biology of Disease

Hypoxia-inducible Factor-dependent Regulation of Platelet-activating Factor Receptor as a Route for Gram-Positive Bacterial Translocation across Epithelia

Simon Keely*,{dagger}, Louise E. Glover*,{dagger}, Thomas Weissmueller*, Christopher F. MacManus*, Sophie Fillon{ddagger}, Blair Fennimore*, and Sean P. Colgan*

*Mucosal Inflammation Program, Department of Medicine, University of Colorado Denver, Aurora, CO 80045; and {ddagger}Section of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital, University of Colorado Denver School of Medicine, Aurora, CO 80045

Received for publication July 16, 2009. Revision received November 9, 2009. Accepted for publication December 14, 2009.

Monitoring Editor: Asma Nusrat

Abstract: Mucosal surfaces, such as the lung and intestine, are lined by a monolayer of epithelia that provides tissue barrier and transport function. It is recently appreciated that a common feature of inflammatory processes within the mucosa is hypoxia (so-called inflammatory hypoxia). Given the strong association between bacterial translocation and mucosal inflammatory disease, we hypothesized that intestinal epithelial hypoxia influences bacterial translocation. Initial studies revealed that exposure of cultured intestinal epithelia to hypoxia (pO2, 20 torr; 24–48 h) resulted in a increase of up to 40-fold in the translocation of some strains of Gram-positive bacteria, independently of epithelial barrier function. A screen of relevant pathway inhibitors identified a prominent role for the platelet-activating factor receptor (PAFr) in hypoxia-associated bacterial translocation, wherein pharmacologic antagonists of PAFr blocked bacterial translocation by as much as 80 ± 6%. Extensions of these studies revealed that hypoxia prominently induces PAFr through a hypoxia-inducible factor (HIF)-dependent mechanism. Indeed, HIF and PAFr loss of function studies (short hairpin RNA) revealed that apically expressed PAFr is central to the induction of translocation for the Gram-positive bacteria Enterococcus faecalis. Together, these findings reveal that some strains of Gram-positive bacteria exploit HIF-regulated PAFr as a means for translocation through intestinal epithelial cells.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-07-0573) on December 23, 2009.

{dagger} These authors contributed equally to this work.

Address correspondence to: Simon Keely (simon.keely{at}ucdenver.edu) or Sean P. Colgan (sean.colgan{at}ucdenver.edu)

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