Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes
Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes
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DOI：
10.1046/j.0022-202x.2001.01573.x
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发表时间：
2001-12-01
影响因子：
6.5
通讯作者：
Kaufmann, R
中科院分区：
文献类型：
--
作者：
Gille, J;Reisinger, K;Kaufmann, R
表皮角化细胞衍生的血管内皮生长因子的过表达在功能上与迂曲和高渗透性真皮微血管密度增加相关，代表皮肤炎症的特征性组分。我们推测，合成糖皮质激素的强效抗炎特性部分归因于它们对角质形成细胞调节的血管内皮生长因子表达的干扰。由于血管内皮生长因子被自分泌转化生长因子α和旁分泌肝细胞生长因子/分散因子表达显著上调，因此检测了糖皮质激素对生长因子诱导的原代和永生化角质形成细胞产生血管内皮生长因子的影响。糖皮质激素以浓度和时间依赖性方式抑制血管内皮生长因子蛋白和mRNA的表达。然而，在转录激活研究中，血管内皮生长因子基因的共同5 '调控区未能赋予抑制性糖皮质激素作用。相反，糖皮质激素显示增加血管内皮生长因子mRNA周转，表明糖皮质激素作用的转录后模式用于负调节诱导的血管内皮生长因子表达。总之，这些研究确定了表皮角质形成细胞上调血管内皮生长因子作为皮肤炎症中糖皮质激素作用的假定靶点。我们的数据提供了强有力的证据表明，mRNA的不稳定可能是糖皮质激素抑制角质形成细胞的生长因子调节的血管内皮生长因子基因表达的一种机制。
Epidermal keratinocyte-derived overexpression of vascular endothelial growth factor has been functionally linked to increased density of tortuous and hyperpermeable dermal microvessels, representing a characteristic component of cutaneous inflammation. We hypothesized that potent anti-inflammatory properties of synthetic glucocorticoids are attributed in part to their interference with the regulated vascular endothelial growth factor expression by keratinocytes. As vascular endothelial growth factor is markedly upregulated by autocrine transforming growth factor alpha and paracrine hepatocyte growth factor/scatter factor expression, the effect of glucocorticoids on growth-factor-induced vascular endothelial growth factor production by primary and immortalized keratinocytes was examined. Glucocorticoids were shown to suppress vascular endothelial growth factor protein and mRNA expression in a concentration- and time-dependent fashion. In transcriptional activation studies, however, common 5'-regulatory regions of the vascular endothelial growth factor gene failed to confer inhibitory glucocorticoid effects. Instead, glucocorticoids were shown to increase vascular endothelial growth factor mRNA turnover, indicating that post-transcriptional modes of glucocorticoid action are employed to negatively regulate induced vascular endothelial growth factor expression. Together, these studies identify vascular endothelial growth factor upregulation by epidermal keratinocytes as a putative target of glucocorticoid action in cutaneous inflammation. Our data provide strong evidence that mRNA destabilization may represent a mechanism by which glucocorticoids inhibit growth-factor-regulated vascular endothelial growth factor gene expression by keratinocytes.