REGULATION OF DIFFERENTIATION IN LUNG AND EPIDERMAL KERATINOCYTES

类维生素a在调节气管支气管上皮细胞的分化和增殖中起重要作用。在缺乏类维生素a的情况下，细胞会发生鳞状分化，这可以通过几种鳞状细胞标志物的表达来表明，包括上皮膜蛋白EMP-1或CL20。视黄酸（RA）处理正常人气管支气管上皮（HTBE）细胞抑制鳞状细胞分化，诱导粘膜细胞分化，通过抑制转谷氨酰胺酶I和增加粘蛋白基因MUC2的表达表明。后者伴随着参与RA分解代谢的细胞色素P450基因CYP26的表达增加。虽然RA是必需的，但不足以诱导RARb、CYP26和MUC2 mRNA，因为诱导仅在融合培养中观察到，而在对数培养中没有观察到，这表明其他因素在它们的调节中起关键作用。CYP26 mRNA可被rar选择性类维甲酸TTAB诱导，但不能被rxr选择性类维甲酸SR11217或抗ap1选择性类维甲酸SR11302诱导。RARa-， b-和g选择性类维生素a能够诱导CYP26，这种诱导被RARa选择性拮抗剂Ro41-5253抑制。TTAB仅能在少数肺癌细胞系中诱导CYP26 mRNA的表达。在许多癌细胞系中缺乏CYP26诱导可能与先前报道的类维甲酸信号通路缺陷有关。CYP26的诱导与RA代谢增加成18-羟基、4-氧和4-羟基RA相关。后一种代谢物能够诱导HTBE细胞中MUC2和MUC5AC的表达。我们的研究结果表明，在正常HTBE细胞中，CYP26的表达与粘液细胞分化密切相关。

Retinoids are important in the regulation of differentiation and proliferation of tracheobronchial epithelial cells. In the absence of retinoids cell undergo squamous differentiation as indicated by the expression of several squamous cell markers including the epithelial membrane protein EMP-1 or CL20. Treatment of normal human tracheobronchial epithelial (HTBE) cells with retinoic acid (RA) inhibits squamous differentiation and induces mucous cell differentiation as indicated by the suppression of transglutaminase I and increased expression of the mucin gene MUC2. The latter is accompanied by increased expression of cytochrome P450 gene CYP26 which is involved in RA catabolism. Although RA is required, it is not sufficient to induce RARb, CYP26, and MUC2 mRNA since induction is only observed in confluent but not in logarithmic cultures suggesting that additional factors are critical in their regulation. CYP26 mRNA can be induced by the RAR-selective retinoid TTAB but not by the RXR-selective retinoid SR11217 or the anti-AP1-selective retinoid SR11302. RARa-, b-, and g-selective retinoids are able to induce CYP26, this induction is inhibited by the RARa-selective antagonist Ro41-5253. TTAB is able to induce CYP26 mRNA expression in only a few of the lung carcinoma cell lines tested. The lack of CYP26 induction in many carcinoma cell lines may relate to previously reported defects in the retinoid-signaling pathway. The induction of CYP26 correlated with increased metabolism of RA into 18-hydroxy-, 4-oxo-, and 4-hydroxy-RA. The latter metabolite was shown to be able to induce MUC2 and MUC5AC expression in HTBE cells. Our results demonstrate that in normal HTBE cells CYP26 expression is closely associated with mucous cell differentiation.