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Autocrine mechanism of GM-CSF production in human fibroblasts

人成纤维细胞产生 GM-CSF 的自分泌机制

基本信息

批准号：
04671542
负责人：
AKASHI Makoto
金额：
$ 1.41万
依托单位：
NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671542/
关键词：
human fibroblasts GM-CSF autocrine stimulationm mRNA constitutive expression 自己刺激線維芽細胞

项目摘要

Prior study by us found that expression of GM-CSF mRNA in human embryonic lung fibroblasts W138 is regulated through an autocrine stimulation by IL-1 production. In the present study, we showed that expression of manganese superoxide dismutase (MnSOD) gene is also regulated by an autocrine mechanism in these cells ; treatment of cells with either anti-IL-1 alpha or beta antibody reduced the constitutive expession of MnSOD mRNA.These results indicate that the autocrine stimulation may be one of the important mechanisms in expression of genes as well as GM-CSF.To further investigate the role of IL-1 in induction of GM-CSF or MnSOD,cells were irradiated in the presence of anti-IL-1 antibody. Irradiation increased the levels of GM-CSF and MnSOD mRNAs in a dose- and time-dependent fashion. Treatment with anti-IL-1 antibody blocked the induction of these mRNAs in these cells and exogenously added-IL-1 increased the levels of these mRNAs. Similar results were also obtained in the experiment using human monocytic cells THP-1. Irradiation increased the production of tumor necrosis factor (TNF) in a dose dependent manner. Irradiation induced the expression of MnSOD mRNA and treatment of these cells with anti-TNF antibody inhibited the induction of MnSOD mRNA by irradiation. Furthermore, we also found that irradiation increased expression of WAF1/CIP1, p21, through the production of TNF in human myeloblastic cells KG1. Our present studies indicate an autocrine or paracrine mechanism (s) may play an important role in expression of genes in various cells.

我们先前的研究发现，人胚肺成纤维细胞W138中GM-CSF mRNA的表达是通过IL-1的自分泌刺激来调节的。在本研究中，我们发现在这些细胞中，锰超氧化物歧化酶(MnSOD)基因的表达也受自分泌机制的调控；抗IL-1α或β抗体处理细胞后，MnSODmRNAs的组成性表达减少。这些结果表明，自分泌刺激可能是GM-CSF和GM-CSF基因表达的重要机制之一。为了进一步研究IL-1在诱导GM-CSF或MnSOD中的作用，在抗IL-1抗体的存在下对细胞进行照射。照射后GM-CSF和MnSODmRNAs水平增加，呈剂量和时间依赖关系。用抗IL-1抗体处理可阻断这些细胞中这些mRNAs的诱导，而外源性添加IL-1可增加这些mRNAs的水平。在用人单核细胞THP-1进行的实验中也得到了类似的结果。照射可增加肿瘤坏死因子的产生，并呈剂量依赖关系。辐射可诱导细胞表达MnSODmRNA，抗肿瘤坏死因子抗体可抑制辐射诱导的MnSODmRNA表达。此外，我们还发现，照射通过在人成髓细胞KG1中产生肿瘤坏死因子而增加WAF1/CIP1、p21的表达。我们目前的研究表明，自分泌或旁分泌机制(S)可能在各种细胞的基因表达中发挥重要作用。