Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0109006 on May 28, 2009

Published online before print May 28, 2009
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(Journal of Leukocyte Biology. 2009;86:959-969.)
© 2009 Society for Leukocyte Biology

All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis

Aiping Bai*,{dagger},1, Nonghua Lu*, Yuan Guo*, Zhanju Liu{ddagger}, Jiang Chen* and Zhikang Peng{dagger}

* Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang City, China;
{dagger} Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada; and
{ddagger} Department of Gastroenterology, Shanghai Tenth People’s Hospital, Shanghai, China

1. Correspondence: Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang 330006, China. E-mail: baiap{at}163.com

ABSTRACT

IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RAR{alpha}, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RAR{alpha} or LE135 as the antagonist of RAR{alpha}. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-{alpha}, IL-1β, IL-17) but more regulatory cytokines (IL-10, TGF-β) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.

Key Words: inflammatory bowel disease • IL-17 • FOXP3 • RAR{alpha} • TNBS