Retinoic acid attenuates ileitis by restoring the balance between T-helper 17 and T regulatory cells.

Abstract

BACKGROUND & AIMS:

Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells.

METHODS:

We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF_ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry.

RESULTS:

Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells.

CONCLUSIONS:

Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease.

• Authors: Colm B Collins, Carol M Aherne, Douglas Kominsky, Eóin N McNamee, Matthew D P Lebsack, Holger Eltzschig, Paul Jedlicka, Jesús Rivera-Nieves
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 5 Pg. 1821-31 (Nov 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 22027263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• Cytokines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Integrin alpha Chains
• alpha E integrins
• Tretinoin

Topics

• Animals
• Antigens, CD (metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coculture Techniques
• Cytokines (metabolism)
• Dendritic Cells (drug effects, metabolism, pathology)
• Disease Models, Animal
• Forkhead Transcription Factors (metabolism)
• Ileitis (drug therapy, pathology)
• Integrin alpha Chains (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Mice, Knockout
• T-Lymphocytes, Regulatory (drug effects, metabolism, pathology)
• Th17 Cells (drug effects, pathology)
• Tretinoin (pharmacology, therapeutic use)