Analysis of the mechanism for regulation of interleukin 2 gene expression

白细胞介素2基因表达调控机制分析

基本信息

批准号：
61570241
负责人：
ONOUE Kaoru
金额：
$ 1.54万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1987
项目状态：
已结题

项目摘要

Interleukin 2 is a lymphokine essential for the growth and differentiation of lymphocytes. It is particularly important to note that helper T cells can be triggered by antigenic stimulation to express IL 2 and IL 2 receptor genes allowing them to grow by autocrine mechanism. A continued autocrine growth under some circumstances like a retroviral infection is supposed to be related to leukemic transformation of the cells. In this research project we analysed the triggering and regulatory mechanism of the IL 2 and IL 2 receptor expression using human T cells. 1) Studis of the roles of accessory cells (macrophages) required for triggering the peripheral blood T cells by anti-T3 monoclonal antibody revealed that the roles can be dissected into three : First, they present anti-T3 antibodies bound on the Fc receptors to T cells so that multiple interaction between anti-T3 molecules and T cell antigen receptor Ti/T3 molecules may result in the crosslinking of the receptors. Second, a certain … More molecules on macrophage cell surface appears to be required to interact with T cell surface. Our study revealed that the necessary molocules can be induced on U937 cells by recombinant interferon <gamma> (rIFN-<gamma>). Third, soluble factors released from macropages are essential for T cell triggering. Although the molecular nature of the factors are not yet determined, the combination of IL 1 and IL 6 were shown to replace macrophage factors. It was clarified that the IL 2 mRNA production can be induced only when the accessory cells fulfill the above three requirements. 2) Activation of protein kinase C was shown to play a critical role in regulating the magnitute of IL 2 gene expression. Thus a close correlation between the dose responses of protein kinase C activation and IL 2 mRNA production was observed. 3) In stimulated T cells, the IL 2 mRNA produced persists longer in cytoplasm than in the unstimulated T cells. 4) Cyclosporin A inhibits the induction of IL 2 mRN@a production without affecting Ca_<2+> mobilization and protein C kinase activation. 5) Two cases of adult T cell leukemia (ATL) patients were found whose leukemic cells produced IL 2 mRNA and IL 2 without any stimulation in culture and showing an autocrine growth in response to IL 2 produced by themselves, suggesting that the autocrine mechanism may be an inportant process in leukemogensis. Less

白细胞介素2是淋巴细胞生长和分化至关重要的淋巴因子。尤其重要的是要注意，可以通过抗原刺激触发辅助T细胞来表达IL 2和IL 2受体基因，从而使其通过自分泌机制生长。在某些情况下，诸如逆转录病毒感染（例如细胞的白血病转化）等在某些情况下的持续自分泌生长。在该研究项目中，我们分析了使用人T细胞的IL 2和IL 2受体表达的触发和调节机制。 1) Studis of the roles of accessory cells (macrophages) required for triggering the peripheral blood T cells by anti-T3 monoclonal antibody revealed that the roles can be dissected into three : First, they present anti-T3 antibodies bound on the Fc receptors to T cells so that multiple interaction between anti-T3 molecules and T cell antigen receptor Ti/T3 molecules may result in the crosslinking接收器。其次，与T细胞表面相互作用似乎需要一定的……更多的巨噬细胞表面分子。我们的研究表明，重组干扰素<gamma>（RIFN- <gamma>）可以在U937细胞上诱导必要的大麻。第三，从宏观释放的固体因子对于T细胞触发至关重要。尽管尚未确定因子的分子性质，但IL 1和IL 6的组合被证明可以替代巨噬细胞因子。可以澄清的是，只有当辅助细胞满足以上三个要求时，才能诱导IL 2 mRNA的产生。 2）蛋白激酶C的激活在调节IL 2基因表达中起着至关重要的作用。观察到蛋白激酶C活化的剂量反应与IL 2 mRNA的产生之间的密切相关。 3）在受刺激的T细胞中，IL 2 mRNA在细胞质中的持续时间比未刺激的T细胞更长。 4）环孢菌素A抑制IL 2 mRN@A的诱导，而不会影响CA__ <2+>动员和蛋白C激酶激活。 5）发现两例成人T细胞白血病（ATL）患者的患者的白血病细胞是在培养中没有任何刺激的IL 2 mRNA和IL 2产生的，并显示出对自身产生的IL 2的自身分泌生长，这表明自身分泌机制可能是白血病的重要过程。