IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion
IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion
复制标题
DOI：
10.1111/j.1600-0625.2011.01412.x
复制
发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Ogg, Graham S.
中科院分区：
文献类型：
--
作者：
Gutowska-Owsiak, Danuta;Schaupp, Anna L.;Ogg, Graham S.
特应性湿疹和牛皮癣是常见的皮肤病。虽然众所周知，这些疾病的发病机制各不相同，但两者的特点都是表皮屏障功能受损，皮肤和外周血中IL-17表达异常。最近的研究结果表明，微丝蛋白在屏障的形成过程中是必不可少的，而它的不足是特应性湿疹发病的基础。微丝蛋白下调在牛皮癣中的作用也有报道。很明显，Th1/Th2偏向影响该蛋白的表达，但关于白细胞介素17(IL-17)对该蛋白和Profilaggrin处理酶表达的影响的分析尚未见报道。此外，细胞因子对功能性表皮屏障成分、紧密连接和黏附/桥粒蛋白的影响尚未阐明。角质形成细胞暴露于白介素17A，并进行基因芯片分析。免疫印迹法检测微丝蛋白表达水平。我们观察到，在白介素17A暴露的培养物中，profilaggrin基因水平显著降低(P=0.008)。加工酶的表达也发生了变化，表明细胞因子对微丝蛋白的产生/降解有间接影响。此外，许多参与细胞黏附的基因的表达也减少了。免疫印迹检测到永生化角质形成细胞和原代角质形成细胞中微丝蛋白在蛋白水平显著下调。基因本体论分析表明角质化、表皮分化和角化包膜的形成发生了变化。我们的结论是，IL-17A下调微丝蛋白和细胞黏附重要基因的表达，这可能会影响表皮屏障的形成。这种作用可能会导致屏障功能障碍，并可能成为可能的治疗靶点。
Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1/Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion/desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production/degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.