Hypoxia-inducible Factor 1-dependent Induction of Intestinal Trefoil Factor Protects Barrier Function during Hypoxia

doi:10.1084/jem.193.9.1027

Published online 30 April 2001.

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© The Rockefeller University Press, 0022-1007/2001/5/1027/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 9, May 7, 2001 1027-1034

Original Article

Hypoxia-inducible Factor 1–dependent Induction of Intestinal Trefoil Factor Protects Barrier Function during Hypoxia

Glenn T. Furuta^a,c, Jerrold R. Turner^e, Cormac T. Taylor^a, Robert M. Hershberg^b, Katrina Comerford^a, Sailaja Narravula^a, Daniel K. Podolsky^d, and Sean P. Colgan^a
^a Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, the
^b Division of Gastroenterology, Brigham and Women's Hospital, the
^c Combined Program for Pediatric Gastroenterology and Nutrition, Children's Hospital,
^d Gastrointestinal Unit and Center for Study of Inflammatory Bowel Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115
^e Department of Pathology, Wayne State University, Detroit, Michigan 48201

Correspondence to: Sean P. Colgan, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Thorn Bldg. 704, 20 Shattuck St., Boston, MA 02115. Tel:617-732-5500 ext. 1401 Fax:617-278-6957 E-mail:colgan{at}zeus.bwh.harvard.edu.

Mucosal organs such as the intestine are supported by a richand complex underlying vasculature. For this reason, the intestine,and particularly barrier-protective epithelial cells, are susceptibleto damage related to diminished blood flow and concomitant tissuehypoxia. We sought to identify compensatory mechanisms thatprotect epithelial barrier during episodes of intestinal hypoxia.Initial studies examining T84 colonic epithelial cells revealedthat barrier function is uniquely resistant to changes elicitedby hypoxia. A search for intestinal-specific, barrier-protectivefactors revealed that the human intestinal trefoil factor (ITF)gene promoter bears a previously unappreciated binding sitefor hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallelinduction of ITF mRNA and protein. Electrophoretic mobilityshift assay analysis using ITF-specific, HIF-1 consensus motifsresulted in a hypoxia-inducible DNA binding activity, and loadingcells with antisense oligonucleotides directed against the ${alpha}$ chain of HIF-1 resulted in a loss of ITF hypoxia inducibility.Moreover, addition of anti-ITF antibody resulted in a loss ofbarrier function in epithelial cells exposed to hypoxia, andthe addition of recombinant human ITF to vascular endothelialcells partially protected endothelial cells from hypoxia-elicitedbarrier disruption. Extensions of these studies in vivo revealedprominent hypoxia-elicited increases in intestinal permeabilityin ITF null mice. HIF-1–dependent induction of ITF mayprovide an adaptive link for maintenance of barrier functionduring hypoxia.

Key Words: epithelium, gastrointestinal disease, transcription factor,intestinal permeability, endothelium

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