Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T
Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Biochem Biophys Res Commun. 1995 Jun 15;211(2):396-403. doi: 10.1006/bbrc.1995.1827.
ISP-1/myriocin is a new type of remarkably potent immunosuppressant, the structure of which is homologous to sphingosine. ISP-1/myriocin inhibited the proliferation of an IL-2-dependent mouse cytotoxic T cell line, CTLL-2, at nanomole concentrations. ISP-1/myriocin inhibits serine palmitoyltransferase activity at picomole concentrations. This enzyme catalyzes the first step of sphingolipid biosynthesis and reduces the intracellular pool of sphingolipid intermediates. The growth inhibition induced by ISP-1/myriocin was completely abolished by the addition of sphingosines or sphingosine-1-phosphate, but not by sphingomyelin or glycosphingolipids. These results suggest that sphingosines or sphingosine-1-phosphate are associated with CTLL-2 proliferation, and ISP-1/myriocin suppresses T cell proliferation by the modulation of sphingolipid metabolism. ISP-1/myriocin should be a useful tool for the study of the sphingolipid pathway, which has been associated with various kinds of signal transduction.
ISP-1/嗜热栖热放线菌素是一种新型的强效免疫抑制剂，其结构与鞘氨醇同源。ISP-1/嗜热栖热放线菌素在纳摩尔浓度下就能抑制依赖白细胞介素-2的小鼠细胞毒性T细胞系CTLL-2的增殖。ISP-1/嗜热栖热放线菌素在皮摩尔浓度下就能抑制丝氨酸棕榈酰转移酶的活性。该酶催化鞘脂生物合成的第一步，并减少细胞内鞘脂中间体的库。添加鞘氨醇或鞘氨醇-1-磷酸可完全消除ISP-1/嗜热栖热放线菌素诱导的生长抑制，但鞘磷脂或糖鞘脂则不能。这些结果表明，鞘氨醇或鞘氨醇-1-磷酸与CTLL-2增殖有关，而ISP-1/嗜热栖热放线菌素通过调节鞘脂代谢来抑制T细胞增殖。ISP-1/嗜热栖热放线菌素应该是研究与各种信号转导相关的鞘脂途径的有用工具。
