Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients
Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients
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DOI：
10.1111/exd.12986
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发表时间：
2016-05-01
影响因子：
3.6
通讯作者：
Wenzel, Joerg
中科院分区：
文献类型：
--
作者：
Braegelmann, Christine;Hoelzel, Michael;Wenzel, Joerg
脾酪氨酸激酶（SYK）是一种参与细胞增殖和炎症途径调节的蛋白激酶。由于越来越多的证据表明激酶抑制剂具有作为特异性抗炎药物的潜力，我们已经研究了SYK抑制作为自身免疫性疾病，特别是皮肤红斑狼疮（CLE）的治疗靶点的潜力。通过基因表达分析和免疫组织化学分析不同CLE亚型患者和适当对照的皮肤样品的SYK和SYK相关促炎介质的表达。使用LE-典型的促炎刺激和SYK的选择性抑制剂，在体外研究了SYK在角质形成细胞中的功能作用。SYK相关基因在CLE皮肤病变中强烈上调。重要的是，磷酸化SYK（pSYK）由几种免疫细胞类型以及CLE皮肤中的角质形成细胞强烈表达。在体外，免疫刺激性核酸能够诱导角质形成细胞中的SYK磷酸化，导致促炎细胞因子的诱导，而小分子SYK抑制降低这些蛋白质的表达。结果表明pSYK由CLE患者皮肤病变中的免疫细胞和角质形成细胞表达。LE-典型刺激诱导pSYK在体外的表达。小分子SYK抑制导致角质形成细胞中pSYK表达的减少和促炎细胞因子的下调。因此，我们认为pSYK为治疗患有CLE和相关皮肤疾病的患者提供了潜在的未来药物靶点。具体来说，我们的研究揭示了支持使用局部SYK抑制剂治疗狼疮的证据。
Spleen tyrosine kinase (SYK) is a protein kinase involved in cell proliferation and the regulation of inflammatory pathways. Due to the increasing evidence that kinase inhibitors have potential as specific anti-inflammatory drugs, we have investigated the potential for SYK inhibition as a therapeutic target in autoimmune diseases, particularly cutaneous lupus erythematosus (CLE). Skin samples of patients with different CLE subtypes and appropriate controls were analysed for the expression of SYK and SYK-associated pro-inflammatory mediators via gene expression analysis and immunohistochemistry. The functional role of SYK in keratinocytes was investigated in vitro, using LE-typical pro-inflammatory stimuli and a selective inhibitor of SYK. SYK-associated genes are strongly upregulated in CLE skin lesions. Importantly, phosphorylated SYK (pSYK) is strongly expressed by several immune cell types and also keratinocytes in CLE skin. In vitro, immunostimulatory nucleic acids are capable of inducing SYK phosphorylation in keratinocytes leading to the induction of pro-inflammatory cytokines, while small-molecule SYK inhibition decreases the expression of these proteins. The results demonstrate that pSYK is expressed by immune cells and keratinocytes in skin lesions of CLE patients. LE-typical stimuli induce the expression of pSYK in vitro. Small-molecule SYK inhibition leads to a reduction of pSYK expression and downregulation of pro-inflammatory cytokines in keratinocytes. We therefore believe that pSYK provides a potential future drug target for the treatment of patients who suffer from CLE and related skin disorders. Specifically, our study reveals evidence supporting the use of topical SYK inhibitors in treating lupus.