Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia

Glenn T. Furuta, Jerrold R. Turner, Cormac T. Taylor, Robert M. Hershberg, Katrina Comerford, Sailaja Narravula, Daniel K. Podolsky, Sean P. Colgan

Research output: Contribution to journalArticle

270 Citations (Scopus)

Abstract

Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1-dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.

Original languageEnglish (US)
Pages (from-to)1027-1034
Number of pages8
JournalJournal of Experimental Medicine
Volume193
Issue number9
DOIs
StatePublished - May 7 2001

Fingerprint

Hypoxia-Inducible Factor 1
Epithelial Cells
Intestines
Endothelial Cells
Trefoil Factor-3
Hypoxia
Cell Hypoxia
Antisense Oligonucleotides
Electrophoretic Mobility Shift Assay
Permeability
Binding Sites
Maintenance
Messenger RNA

Keywords

  • Endothelium
  • Epithelium
  • Gastrointestinal disease
  • Intestinal permeability
  • Transcription factor

ASJC Scopus subject areas

  • Immunology

Cite this

Furuta, G. T., Turner, J. R., Taylor, C. T., Hershberg, R. M., Comerford, K., Narravula, S., ... Colgan, S. P. (2001). Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. Journal of Experimental Medicine, 193(9), 1027-1034. https://doi.org/10.1084/jem.193.9.1027

Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. / Furuta, Glenn T.; Turner, Jerrold R.; Taylor, Cormac T.; Hershberg, Robert M.; Comerford, Katrina; Narravula, Sailaja; Podolsky, Daniel K.; Colgan, Sean P.

In: Journal of Experimental Medicine, Vol. 193, No. 9, 07.05.2001, p. 1027-1034.

Research output: Contribution to journalArticle

Furuta, GT, Turner, JR, Taylor, CT, Hershberg, RM, Comerford, K, Narravula, S, Podolsky, DK & Colgan, SP 2001, 'Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia', Journal of Experimental Medicine, vol. 193, no. 9, pp. 1027-1034. https://doi.org/10.1084/jem.193.9.1027
Furuta, Glenn T. ; Turner, Jerrold R. ; Taylor, Cormac T. ; Hershberg, Robert M. ; Comerford, Katrina ; Narravula, Sailaja ; Podolsky, Daniel K. ; Colgan, Sean P. / Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. In: Journal of Experimental Medicine. 2001 ; Vol. 193, No. 9. pp. 1027-1034.
@article{5addfc45674840c3bf1ecc3f870d68a7,
title = "Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia",
abstract = "Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1-dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.",
keywords = "Endothelium, Epithelium, Gastrointestinal disease, Intestinal permeability, Transcription factor",
author = "Furuta, {Glenn T.} and Turner, {Jerrold R.} and Taylor, {Cormac T.} and Hershberg, {Robert M.} and Katrina Comerford and Sailaja Narravula and Podolsky, {Daniel K.} and Colgan, {Sean P.}",
year = "2001",
month = "5",
day = "7",
doi = "10.1084/jem.193.9.1027",
language = "English (US)",
volume = "193",
pages = "1027--1034",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "9",

}

TY - JOUR

T1 - Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia

AU - Furuta, Glenn T.

AU - Turner, Jerrold R.

AU - Taylor, Cormac T.

AU - Hershberg, Robert M.

AU - Comerford, Katrina

AU - Narravula, Sailaja

AU - Podolsky, Daniel K.

AU - Colgan, Sean P.

PY - 2001/5/7

Y1 - 2001/5/7

N2 - Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1-dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.

AB - Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1-dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia.

KW - Endothelium

KW - Epithelium

KW - Gastrointestinal disease

KW - Intestinal permeability

KW - Transcription factor

UR - http://www.scopus.com/inward/record.url?scp=0035821249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035821249&partnerID=8YFLogxK

U2 - 10.1084/jem.193.9.1027

DO - 10.1084/jem.193.9.1027

M3 - Article

C2 - 11342587

AN - SCOPUS:0035821249

VL - 193

SP - 1027

EP - 1034

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 9

ER -