Million K, Tournier F, Houcine O, Ancian P, Reichert U, Marano F
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Paris; and Galderma, Research and Development, Valbonne, France.
Am J Respir Cell Mol Biol. 2001 Dec;25(6):744-50. doi: 10.1165/ajrcmb.25.6.4549.
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 RARalpha, RARbeta, and RARgamma, 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.
维甲酸在上呼吸道上皮细胞的黏液纤毛表型维持中起关键作用。为了确定维甲酸受体（RARs）在上皮细胞分化调节中的作用，我们在体外人鼻上皮（HNE）细胞分化过程中，分别测试了合成维甲酸CD336、CD2019和CD666（分别为RARα、RARβ和RARγ的选择性激动剂）的作用。分别使用谷氨酰胺化微管蛋白和转谷氨酰胺酶I（Tg I）作为纤毛细胞和鳞状细胞分化的标志物，我们发现维甲酸（RA）刺激黏液纤毛分化，同时抑制鳞状细胞分化。三种RARs的激动剂通过以剂量和时间依赖性方式下调Tg I表达，独立诱导纤毛生成并抑制鳞状细胞分化。三种RARs的特异性拮抗剂消除了相应激动剂的作用，证明了RAR特异性介导的效应。此外，用RAR激动剂处理缺乏维甲酸的培养物可诱导鳞状样表型转变为纤毛表型。总之，所有三种RARs都可能参与RA对呼吸道上皮细胞的分化作用。
