ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fc epsilon receptor 1-mediated activation of Syk
ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fc epsilon receptor 1-mediated activation of Syk
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DOI：
10.1073/pnas.94.23.12539
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发表时间：
1997-11-11
影响因子：
11.1
通讯作者：
Yamada, K
中科院分区：
文献类型：
--
作者：
Moriya, K;Rivera, J;Yamada, K
与肥大细胞免疫球蛋白E （IgE）高亲和受体Fc epsilon RI结合，诱导Syk的酪氨酸磷酸化，Syk是一种非受体酪氨酸激酶，已被证明对脱粒至关重要。在这里，我们描述了一种合成化合物ER-27319，作为抗原或抗IgE介导的啮齿动物和人类肥大细胞脱粒的有效和选择性抑制剂。ER-27319既不影响Lyn激酶活性，也不影响抗原诱导的Fc epsilon RI的磷酸化，但却有效抑制Syk的酪氨酸磷酸化，从而抑制Syk的活性。因此，酪氨酸磷酸化的磷脂酶c - γ 1、肌醇磷酸的生成、花生四烯酸的释放、组胺和肿瘤坏死因子α的分泌也受到抑制。ER-27319不抑制Jurkat T细胞中抗cd3诱导的磷脂酶c - γ 1的酪氨酸磷酸化，表明对Syk诱导的信号具有特异性。相反，用Fc epsilon RI γ亚基磷酸化的免疫受体酪氨酸激活基元（ITAM）或rbr - 2h3细胞的抗原激活诱导的Syk的酪氨酸磷酸化和激活，ER-27319特异性抑制。当ER-27319加入到免疫沉淀的Syk中，对Syk活性没有影响，ER-27319不抑制Ig β ITAM激活诱导的Syk酪氨酸磷酸化，也不抑制抗igm诱导的人外周血B细胞中Syk的磷酸化，因此，ER-27319选择性地干扰了体外和完整细胞中Syk的Fc epsilon RI γ磷酸化ITAM激活。这些结果证实了Syk在肥大细胞中Fc epsilon ri介导的应答中的重要性，并证明了ER-27319在治疗过敏性疾病中的肥大细胞选择性和治疗潜力。
Engagement of the mast cell high-affinity receptor for immunoglobulin E (IgE), Fc epsilon RI, induces tyrosine phosphorylation of Syk, a non-receptor tyrosine kinase, that has been demonstrated as critical for degranulation, Herein we describe a synthetic compound, ER-27319, as a potent and selective inhibitor of antigen or anti-IgE-mediated degranulation of rodent and human mast cells, ER-27319 affected neither Lyn kinase activity nor the antigen-induced phosphorylation of the Fc epsilon RI but did effectively inhibit the tyrosine phosphorylation of Syk and thus its activity, As a consequence, tyrosine phosphorylation of phospholipase C-gamma 1, generation of inositol phosphates, release of arachidonic acid, and secretion of histamine and tumor necrosis factor alpha were also inhibited, ER-27319 did not inhibit the anti-CD3-induced tyrosine phosphorylation of phospholipase C-gamma 1 in Jurkat T cells, demonstrating a specificity for Syk-induced signals, In contrast the tyrosine phosphorylation and activation of Syk, induced by in vitro incubation with the phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) of Fc epsilon RI gamma subunit or by antigen activation of RBL-2H3 cells, was specifically inhibited by ER-27319, However, when ER-27319 was added to immunoprecipitated Syk, derived from activated cells, no effect was seen on Syk activity, ER-27319 did not inhibit the tyrosine phosphorylation of Syk induced by activation in the presence of Ig beta ITAM or the anti-IgM-induced phosphorylation of Syk in human peripheral B cells, Therefore, ER-27319 selectively interferes with the Fc epsilon RI gamma phospho-ITAM activation of Syk in vitro and in intact cells, These results confirm the importance of Syk in Fc epsilon RI-mediated responses in mast cells and demonstrate the mast cell selectivity and therapeutic potential of ER-27319 in the treatment of allergic disease.