Song Xiuzu, Xu Aie, Pan Wei, Wallin Brittany, Kivlin Rebecca, Lu Shan, Cao Cong, Bi Zhigang, Wan Yinsheng
Department of Dermatology, the Third Hospital of Hangzhou, Hangzhou, PR China.
Int J Mol Med. 2008 Aug;22(2):229-36.
The most common adverse effects that are related to all-trans retinoic acid (atRA) treatment are irritation and dryness of the skin. atRA therapy is reported to impair barrier function as achieved by trans-epidermal water loss (TEWL). Treatment with nicotinamide prior to initiation of atRA therapy provides additional barrier protection and thus reduces susceptibility of retinoic acid. Our previous studies showed that atRA upregulates aquaporin 3 (AQP3) in cultured human skin keratinocytes and fibroblasts. Others have demonstrated that in atopic dermatitis, overexpression of AQP3 is linked to elevated TEWL and that nicotinamide treatment reduces skin TEWL. In this study, we observed that while atRA upregulates AQP3 expression in cultured human skin keratinocytes (HaCaT cells), nicotinamide attenuates the effect of atRA in a concentration-dependent manner. atRA treatment induces EGFR and ERK activation. PD153035, an EGFR inhibitor, and U0126, an ERK inhibitor, inhibit atRA-induced upregulation of AQP3. Nicotinamide also inhibits atRA-induced activation of EGFR/ERK signal transduction and decreases water permeability by downregulating AQP3 expression. Collectively, our results indicate that the effect of atRA on AQP3 expression is at least partly mediated by EGFR/ERK signaling in cultured human skin keratinocytes. Nicotinamide attenuates atRA-induced AQP3 expression through inhibition of EGFR/ERK signal transduction and eventually decreases water permeability and water loss. Our study provides insights into the molecular mechanism through which nicotinamide reverses the side effects of dryness in human skin after treatment with atRA.
与全反式维甲酸（atRA）治疗相关的最常见不良反应是皮肤刺激和干燥。据报道，atRA疗法会损害经表皮水分流失（TEWL）所实现的屏障功能。在开始atRA治疗之前用烟酰胺进行治疗可提供额外的屏障保护，从而降低维甲酸的易感性。我们之前的研究表明，atRA可上调培养的人皮肤角质形成细胞和成纤维细胞中的水通道蛋白3（AQP3）。其他人已经证明，在特应性皮炎中，AQP3的过度表达与TEWL升高有关，并且烟酰胺治疗可降低皮肤TEWL。在本研究中，我们观察到，虽然atRA上调培养的人皮肤角质形成细胞（HaCaT细胞）中AQP3的表达，但烟酰胺以浓度依赖性方式减弱atRA的作用。atRA治疗可诱导表皮生长因子受体（EGFR）和细胞外信号调节激酶（ERK）激活。EGFR抑制剂PD153035和ERK抑制剂U0126可抑制atRA诱导的AQP3上调。烟酰胺还可抑制atRA诱导的EGFR/ERK信号转导激活，并通过下调AQP3表达降低水通透性。总的来说，我们的结果表明，atRA对AQP3表达的影响至少部分是由培养的人皮肤角质形成细胞中的EGFR/ERK信号传导介导的。烟酰胺通过抑制EGFR/ERK信号转导来减弱atRA诱导的AQP3表达，并最终降低水通透性和水分流失。我们的研究为烟酰胺逆转atRA治疗后人体皮肤干燥副作用的分子机制提供了见解。
