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首页> 外文期刊>Cellular immunology >Comparison of the anti-allergic activity of Syk inhibitors with optimized Syk siRNAs in FcepsilonRI-activated RBL-2H3 basophilic cells.
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Comparison of the anti-allergic activity of Syk inhibitors with optimized Syk siRNAs in FcepsilonRI-activated RBL-2H3 basophilic cells.

机译：在FcepsilonRI激活的RBL-2H3嗜碱性细胞中，将Syk抑制剂与优化的Syk siRNA的抗过敏活性进行比较。

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摘要

Spleen tyrosine kinase (Syk) binds ITAM-bearing receptors in a wide variety of cell types. One such example is the activation of mast cells, basophils and eosinophils via the stimulation of the FcepsilonRI receptor by IgE/allergen complexes. The possible role of Syk in inflammatory signaling cascades has led to the development of pharmacological agents designed to block the Syk catalytic domain as potential novel therapeutics. Whilst the enzymatic activity of Syk lends towards the design of small-molecule inhibitors, other attention has focused on the possibility of targeting Syk expression using anti-sense oligonucleotides as an alternate means of anti-inflammatory therapy. In this study, we compared the ability of multiple optimized Syk siRNA sequences and small-molecule Syk inhibitors to block FcepsilonRI-mediated signal transduction, degranulation and TNFalpha secretion in the basophilic cell line RBL-2H3. We also characterized the specificity of each siRNA sequence with regards to off-target induction of the interferon-inducible gene IFIT1. We identified a single siRNA sequence, which displayed a favorable profile of efficient Syk knockdown, blockage of FcepsilonRI-mediated signal transduction, degranulation and TNFalpha secretion and a lack of IFIT1 induction. The effect of this siRNA was comparable to that of the Syk kinase domain inhibitors BAY61-3606 and R406. The identification of an active and specific Syk siRNA could be a basis for the development of therapeutic Syk siRNAs against inflammatory diseases.
机译：脾酪氨酸激酶（Syk）在多种细胞类型中结合带有ITAM的受体。一个这样的例子是通过IgE /过敏原复合物刺激FcepsilonRI受体来激活肥大细胞，嗜碱性粒细胞和嗜酸性粒细胞。 Syk在炎症信号级联反应中的可能作用已导致药理学剂的开发，该药理剂被设计为阻断Syk催化域，作为潜在的新疗法。尽管Syk的酶促活性有助于设计小分子抑制剂，但其他注意力都集中在使用反义寡核苷酸作为抗炎治疗的另一种手段靶向Syk表达的可能性上。在这项研究中，我们比较了多个优化的Syk siRNA序列和小分子Syk抑制剂在嗜碱性细胞系RBL-2H3中阻断FcepsilonRI介导的信号转导，脱粒和TNFalpha分泌的能力。我们还针对干扰素诱导基因IFIT1的脱靶诱导，对每个siRNA序列的特异性进行了表征。我们确定了一个单一的siRNA序列，显示出有效的Syk击倒，FcepsilonRI介导的信号转导，脱粒和TNFalpha分泌的阻滞和缺乏IFIT1诱导的有利情况。此siRNA的作用与Syk激酶域抑制剂BAY61-3606和R406相当。活性和特异性Syk siRNA的鉴定可能是开发针对炎性疾病的治疗性Syk siRNA的基础。

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