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

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 r...

Full description

Saved in:

Bibliographic Details
Published in:	Mucosal immunology 2014-01, Vol.7 (1), p.114-123
Main Authors:	Keely, S, Campbell, E L, Baird, A W, Hansbro, P M, Shalwitz, R A, Kotsakis, A, McNamee, E N, Eltzschig, H K, Kominsky, D J, Colgan, S P
Format:	Article
Language:	eng
Subjects:	Animals Colitis - chemically induced Colitis - drug therapy Colitis - immunology Colitis - metabolism Disease Models, Animal Endotoxemia - drug therapy Female Hypoxia-Inducible Factor 1 - agonists Hypoxia-Inducible Factor 1, alpha Subunit - agonists Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Immunity, Innate - drug effects Immunity, Mucosal - drug effects Intestinal Mucosa - immunology Intestinal Mucosa - metabolism Mice Permeability - drug effects Piperazines - administration & dosage Piperazines - pharmacology Prolyl Hydroxylases - metabolism Prolyl-Hydroxylase Inhibitors - pharmacology Pyridones - administration & dosage Pyridones - pharmacology Trinitrobenzenesulfonic Acid - adverse effects Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	1933-0219 1935-3456