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Study on interleukin 1 signal transduction

白细胞介素1信号转导研究

基本信息

批准号：
08457614
负责人：
ONOZAKI Kikuo
金额：
$ 1.15万
依托单位：
Faculty of Pharmaceutical Sciences, Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457614/
关键词：
IL-1 IL-1R cytokine ODC antizyme melanoma IL-6

项目摘要

IL-1 plays an important role in host reactions, including immunologic, inflammatory and hematologic reactions, and in regulation of cell proliferation and differentiation. In this study we analyzed the mechanism of IL-1 signaling leading to the inhibition of cell proliferation of human melanoma cells A375.1)IL-1 appeared to inhibit the cell proliferation by an increase of AZ,a reguratory factor of ornithine decarboxylase (ODC), both in the levels of transcription and posttranscription other than frameshift. IL-1 also upregulated the activity of p38MAPK which regulated AZ level at the level of posttranscription. The expression levels of cell cycle-regulatory factors, p53, p21 and p16, as well as phosphorylation levels of Rb were not influenced by IL-1.2)By cell hybridization between IL-1 sensitive and resistant cells, resistance to IL-1 appeared to be recessive. In contrast, the constitutive production of IL-1alpha and IL-6 observed in IL-1 resistant cells was dominant. Therefore, in resistant cells the signaling leading to IL-1-induced inhibition of cell proliferation is deficient.3)The characteristics of reported malignant characteristics in human melanoma, including cell adhesion molecules, production of IL-8 and matrix metalloproteinases, invasiveness into matrigel were all incresed in IL-1 resistant cells compared to those of sensitive cells. Therefore, the IL-1 resistant cells apperaed to be a very good model to investigate the mechanism of malignancy of human melanomas.4)By administration of LPS into mice, the expression level of IL-1RI mRNA in the liver was augmented. In this model, IL-1, IL-6 and glucocorticoid (GC) appeared to play an important role. Furthermore, the number of IL-1RI molecule on the cell surface of hepatocytes was increased by treatment with GC and IL-6.

IL-1在宿主反应中起重要作用，包括免疫学、炎症和血液学反应，以及在细胞增殖和分化的调节中。本研究分析了IL-1抑制人黑色素瘤细胞A375增殖的信号转导机制。1）IL-1抑制人黑色素瘤细胞A375增殖的机制可能是通过增加鸟氨酸脱羧酶（ODC）的调节因子AZ，而不是通过移码作用。IL-1还可上调p38 MAPK的活性，从而在转录后水平调节AZ的水平。细胞周期调控因子p53、p21和p16的表达水平以及Rb的磷酸化水平不受IL-1的影响。2）通过IL-1敏感细胞和抗性细胞之间的细胞杂交，对IL-1的抗性表现为隐性。相反，在IL-1抗性细胞中观察到的IL-1 α和IL-6的组成性产生占主导地位。因此，在抗性细胞中，导致IL-1诱导的细胞增殖抑制的信号传导是缺乏的。3）与敏感细胞相比，IL-1抗性细胞中的恶性特征，包括细胞粘附分子，IL-8和基质金属蛋白酶的产生，对基质胶的侵袭性都增加。因此，IL-1抗性细胞是研究人黑色素瘤恶性机制的一个很好的模型。在此模型中，IL-1、IL-6和糖皮质激素（GC）起重要作用。此外，GC和IL-6处理肝细胞表面的IL-1 RI分子的数量增加。