MRC Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Exp Dermatol. 2012 Feb;21(2):104-10. doi: 10.1111/j.1600-0625.2011.01412.x.
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.
特应性皮炎和银屑病是常见的皮肤疾病。虽然这两种疾病的发病机制存在差异，但已明确的是，它们的特征均为表皮屏障功能受损和皮肤及外周血中异常的白细胞介素-17（IL-17）表达。最近的研究结果表明，丝聚蛋白在屏障形成过程中是必需的，其不足是特应性皮炎发病机制的基础。银屑病中也报道了丝聚蛋白的下调。显然，Th1/Th2 偏倚会影响蛋白的表达，但尚未分析白细胞介素-17（IL-17）对蛋白和前丝聚蛋白加工酶的表达的影响。此外，该细胞因子对功能性表皮屏障、紧密连接和黏附/桥粒蛋白成分的影响也尚未阐明。将角质形成细胞暴露于白细胞介素-17A 中，并进行微阵列分析。通过 Western blot 评估丝聚蛋白蛋白水平。我们观察到白细胞介素-17A 暴露培养物中前丝聚蛋白 mRNA 水平显著降低（P = 0.008）。加工酶的表达也发生改变，表明细胞因子对丝聚蛋白产生/降解有间接影响。此外，许多参与细胞黏附的基因的表达也降低。在永生化和原代角质形成细胞中通过 Western blot 检测到丝聚蛋白蛋白水平的显著下调。基因本体分析表明角质化、表皮分化和角蛋白包膜形成发生变化。我们得出结论，IL-17A 下调丝聚蛋白和对细胞黏附重要的基因的表达，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，并可能成为一个潜在的治疗靶点。
