Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D-3 in cultured human epidermal keratinocytes
Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D-3 in cultured human epidermal keratinocytes
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DOI：
10.1111/1523-1747.ep12276488
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发表时间：
1997-07-01
影响因子：
6.5
通讯作者：
Bouillon, R
中科院分区：
文献类型：
--
作者：
Segaert, S;Garmyn, M;Bouillon, R
1，25-二羟维生素D-3（VD）和类维生素A对角质形成细胞增殖都具有有效作用，它们作为类固醇激素的作用（涉及它们的受体的相互作用）和它们对过度增殖性皮肤病的治疗功效的协同作用提供了研究它们对融合前人表皮角质形成细胞培养物中增殖的联合作用的基本原理。[H-3]胸苷掺入法显示，亚药理浓度的全反式维甲酸（atRA）和9-顺式维甲酸（9 cRA）可减弱VD的抗增殖作用，用维甲酸预孵育可明显增强这种作用。细胞周期分析显示，VD处理后细胞出现G1期阻滞，维甲酸（RA）可减弱这种作用。此外，北方和Western印迹分析表明，维甲酸反对VD诱导的转化生长因子β 1，p21（WAF 1）和p27（KIP 1）的积累。最后，维甲酸减少VD引起的视网膜母细胞瘤蛋白的低磷酸化。相反，微摩尔浓度的AtRA增强了大多数上述VD依赖性作用。此外，atRA和9 cRA（但不是VD）引起RXR α蛋白的快速，持续减少。无论是否存在RA，VD均可诱导VD受体蛋白表达。总之，RA调节VD依赖的作用在不同水平的角质形成细胞增殖。这可能对两种药物联合治疗皮肤病产生影响。
Both 1,25-dihydroxyvitamin D-3 (VD) and retinoids have potent effects on keratinocyte proliferation, Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [H-3]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD, Pre-incubation of the cells with the retinoids clearly enhanced this effect, Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta 1, p21(WAF1), and p27(KIP1). Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.