Abstract
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.
Footnotes
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This study was supported by grant (to N.S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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ABBREVIATIONS: TJ, tight junction; atRA, all-trans retinoic acid; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; ZO-1, zonula occludens-1; 9cRA, 9-cis retinoic acid; MDCK, Madin-Darby canine kidney; TER, transepithelial electrical resistance; RT-PCR, reverse transcription-polymerase chain reaction; TNBS, 2,4,6-trinitrobenzene sulfonic acid; DMSO, dimethyl sulfoxide; Am80, 4[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid; Am580, 4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido)benzoic acid; FITC, fluorescein isothiocyanate; PPAR, peroxisome proliferator-activated receptor; FBS, fetal bovine serum.
- Received August 8, 2006.
- Accepted October 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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