Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1
Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1
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DOI：
10.1016/j.bbalip.2005.10.007
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Igarashi, Y
中科院分区：
文献类型：
--
作者：
Kim, JW;Inagaki, Y;Igarashi, Y
抗原诱导的肥大细胞脱颗粒在过敏和炎症反应中起着关键作用。最近，神经酰胺激酶（CERK）及其磷酸化产物神经酰胺1-磷酸（C1 P）已成为肥大细胞脱粒的重要参与者。在这里，我们描述了一种新的F-12509 A烯烃异构体，K1，作为一种有效的CERK抑制剂的合成。体外激酶试验表明，K1有效地抑制CERK，而不抑制鞘氨醇激酶和甘油二酯激酶。用K1处理RBL-2 H3细胞使细胞C1 P水平降低至40%，但对细胞生长没有影响。此外，治疗与K1显着抑制钙离子载体和IgE/抗原诱导的脱粒，表明K1干扰信号发生下游的Ca 2+动员。最后，我们表明K1既不影响IgE/抗原诱导的整体酪氨酸磷酸化，也不影响随后的Ca 2+升高，这表明对CERK介导的信号具有特异性。我们的新型CERK抑制剂为研究CERK和C1 P的生物学功能提供了有用的工具。此外，据我们所知，这是第一份报告表明，抑制CERK抑制IgE/抗原诱导的肥大细胞脱粒。这一发现表明，CERK抑制剂可能是治疗过敏性疾病的潜在治疗工具。(c)2005 Elsevier B. V.保留所有权利。
Antigen-induced degranulation of mast cells plays a pivotal role in allergic and inflammatory responses. Recently, ceramide kinase (CERK) and its phosphorylated product ceramide 1-phosphate (C1P) have emerged as important players in mast cell degranulation. Here, we describe the synthesis of a novel F-12509A olefin isomer, K1, as an effective CERK inhibitor. In vitro kinase assays demonstrated that K1 effectively inhibits CERK without inhibiting sphingosine kinase and diacylglycerol kinase. Treating RBL-2H3 cells with K1 reduced cellular C1P levels to 40% yet had no effect on cell growth. Furthermore, treatment with K1 significantly suppressed both calcium ionophore- and IgE/antigen-induced degranulation, indicating that K1 interferes with signals that happen downstream of Ca2+ mobilization. Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca2+ elevation, suggesting a specificity for CERK-mediated signals. Our novel CERK inhibitor provides a useful tool for studying the biological functions of CERK and C1P. Moreover, to our knowledge, this is the first report demonstrating that inhibition of CERK suppresses IgE/antigen-induced mast cell degranulation. This finding suggests that CERK inhibitors might be a potential therapeutic tool in the treatment of allergic diseases. (c) 2005 Elsevier B.V. All rights reserved.