Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis

Keely, S; Campbell, EL; Baird, AW; Hansbro, PM; Shalwitz, RA; Kotsakis, A; McNamee, EN; Eltzschig, HK; Kominsky, DJ; Colgan, SP

Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis

Keely, S Campbell, EL Baird, AW Hansbro, PM

Shalwitz, RA Kotsakis, A McNamee, EN Eltzschig, HK Kominsky, DJ Colgan, SP

Permalink

Publication Type:: Journal Article
Citation:: Mucosal Immunology, 2014, 7 (1), pp. 114 - 123
Issue Date:: 2014-01-01

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Accepted Manuscript VersionAdobe PDF (212.82 kB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Keely, S	en_US
dc.contributor.author	Campbell, EL	en_US
dc.contributor.author	Baird, AW	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Shalwitz, RA	en_US
dc.contributor.author	Kotsakis, A	en_US
dc.contributor.author	McNamee, EN	en_US
dc.contributor.author	Eltzschig, HK	en_US
dc.contributor.author	Kominsky, DJ	en_US
dc.contributor.author	Colgan, SP	en_US
dc.date.available	2013-04-16	en_US
dc.date.issued	2014-01-01	en_US
dc.identifier.citation	Mucosal Immunology, 2014, 7 (1), pp. 114 - 123	en_US
dc.identifier.issn	1933-0219	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128831
dc.description.abstract	Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by trinitrobenzene sulfonic acid were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi, and clinical, immunological, and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared with vehicle controls. Treated groups were pyrexic but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α-deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies that the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis. © 2014 Society for Mucosal Immunology.	en_US
dc.relation.ispartof	Mucosal Immunology	en_US
dc.relation.isbasedon	10.1038/mi.2013.29	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Intestinal Mucosa	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Endotoxemia	en_US
dc.subject.mesh	Colitis	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Trinitrobenzenesulfonic Acid	en_US
dc.subject.mesh	Piperazines	en_US
dc.subject.mesh	Pyridones	en_US
dc.subject.mesh	Tumor Necrosis Factor-alpha	en_US
dc.subject.mesh	Immunity, Mucosal	en_US
dc.subject.mesh	Permeability	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Hypoxia-Inducible Factor 1	en_US
dc.subject.mesh	Hypoxia-Inducible Factor 1, alpha Subunit	en_US
dc.subject.mesh	Immunity, Innate	en_US
dc.subject.mesh	Prolyl-Hydroxylase Inhibitors	en_US
dc.subject.mesh	Prolyl Hydroxylases	en_US
dc.title	Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	7	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	7	en_US

Abstract:

Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by trinitrobenzene sulfonic acid were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi, and clinical, immunological, and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared with vehicle controls. Treated groups were pyrexic but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α-deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies that the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis. © 2014 Society for Mucosal Immunology.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/128831