Am. J. Respir. Cell Mol. Biol.,
Volume 25, Number 6, December, 2001 744-750
Effects of Retinoic Acid Receptor-Selective Agonists on Human Nasal
Epithelial Cell Differentiation
Karine
Million,
Frédéric
Tournier,
Odile
Houcine,
Philippe
Ancian,
Uwe
Reichert,
and
Francelyne
Marano
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Paris; and Galderma, Research and Development, Valbonne, France
Retinoids play a critical role in the maintenance of the mucociliary phenotype of epithelial cells in the upper respiratory tract.
To determine the role of retinoic acid receptors (RARs) in the
regulation of epithelial differentiation, we tested the effect of
the synthetic retinoids CD336, CD2019, and CD666, selective agonists for RAR
, RAR
, and RAR
, respectively, during differentiation of human nasal epithelial (HNE) cells in vitro. Using
glutamylated tubulin and transglutaminase I (Tg I) as markers
of ciliated cell and squamous cell differentiation, respectively,
we showed that retinoic acid (RA) stimulated mucociliary differentiation and, in parallel, inhibited squamous cell differentiation. The agonists of the three RARs independently induced
ciliogenesis and inhibited squamous cell differentiation by
downregulating Tg I expression in a dose- and time-dependent manner. Antagonists specific for the three RARs abolished
the effects of the corresponding agonists, demonstrating an
RAR-specific mediated effect. Moreover, treatment of retinoid-deficient cultures with RAR agonists induced conversion of the
squamous-like phenotype into a ciliated phenotype. In conclusion, all three RARs are potentially involved in the differentiating effects of RA in respiratory epithelial cells.
Abbreviations: air-liquid interface, ALI; bovine serum albumin, BSA;
Dulbecco's modified Eagle medium, DMEM; fluorescein isothiocyanate, FITC; forward angle scatter, FSC; human nasal epithelial, HNE; phosphate-buffered saline, PBS; retinoic acid, RA; retinoic acid receptor,
RAR; retinoic acid response element, RARE; reverse transcriptase/polymerase chain reaction, RT-PCR; retinoid X receptor, RXR; right angle scatter, SSC; Tris-buffered saline, TBS; transglutaminase I, Tg I.