RT Journal Article
SR Electronic
T1 Cellular Retinoic Acid Bioavailability Determines Epithelial Integrity: Role of Retinoic Acid Receptor α Agonists in Colitis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 250
OP 258
DO 10.1124/mol.106.029579
VO 71
IS 1
A1 Makoto Osanai
A1 Nami Nishikiori
A1 Masaki Murata
A1 Hideki Chiba
A1 Takashi Kojima
A1 Norimasa Sawada
YR 2007
UL http://molpharm.aspetjournals.org/content/71/1/250.abstract
AB The epithelial barrier is determined primarily by intercellular tight junctions (TJs). We have demonstrated previously that all-trans retinoic acid (atRA) plays an important role in forming functional TJs through a specific retinoic acid receptor (RAR)/retinoid X receptor heterodimer in epithelial cells. However, the physiological relevance of retinoic acids (RAs) in maintaining the epithelial integrity remains to be examined. Here, we show that several types of RA, including atRA, promote the barrier function of epithelial TJs. Conversely, RA depletion in the cells by overexpressing CYP26s, cytochrome P450 enzymes specifically involved in the metabolic inactivation of RAs, induces an increase of permeability as measured by two differently sized tracer molecules, inulin and mannitol. This RA-mediated enhancement of barrier function is potentially associated with the increased expression of TJ-associated genes such as occludin, claudin-1, claudin-4, and zonula occludens-1. We also found that RARα is a preferential regulator of the epithelial barrier in vitro. Studies of murine experimental colitis, which is characterized by increased gut permeability, reveal that RARα stimulation significantly attenuates the loss of the epithelial barrier during colitis in vivo. Our results suggest that cellular RA bioavailability determines the epithelial integrity, because it is a critical regulator for barrier protection during mucosal injuries. The American Society for Pharmacology and Experimental Therapeutics