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Analysis of roles of MAP kinase in inflammation and establishment of the target for development of a new anti-inflammatory drug

MAP激酶在炎症中的作用分析及新型抗炎药物开发靶点的建立

基本信息

批准号：
11470481
负责人：
OHUCHI Kazuo
金额：
$ 6.72万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

In the present study, roles of MAP kinases in various responses of inflammatory cells (neutrophils, eosinophils, macrophages, mast cells, epithelial cells) were analyzed. Our findings were as follows: (1) Stimulation of neutrophils with staurosporine induced the production of macrophage inflammatory protein-2 (MIP-2). Both p44/42 MAPK and p38 MAPK participate the stabilization of MIP-2 mRNA and translation of MIP-2 protein. (2) Interleukin-5-induced survival of eosinophils was independent on p44/42 MAPK. In contrast, the apoptosis of the neutrophils infiltrated in the inflammatory sites was mediated by the continuous activation of p38 MAPK. (3) Stimulation of macrophages with staurosporine increased the release of arachidonic acid. The increase in the release of arachidonic acid was due to the phosphorylation of cytosolic phospholipase A_2 by p44/42 MAPK. In addition, in RAW264.7 cells, thapsigargin induced the induction of histidine decarboxylase and histamine production. The transcription of histidine decarboxylase was also regulated by p44/42 MAPK. (4) In mast cells, p38 MAPK partially participated in the antigen-induced interleukin-4 production. (5) MAPKs did not mediate IFN-γ-induced ICAM-1 expression in epithelial cells. In addition, we demonstrated that steroid anti-inflammatory drugs inhibited arachidonic acid release and histamine production in macrophages via inhibiting the activation of MAPKs. MAPK inhibitors showed almost equal inhibitory effect on these responses with the steroid anti-inflammatory drug. These findings suggest that MAPK is one of the targets for development of a new anti-inflammatory drug.

本研究分析了MAP激酶在炎症细胞(中性粒细胞、嗜酸性粒细胞、巨噬细胞、肥大细胞、上皮细胞)的不同反应中的作用。我们的研究结果如下：(1)星形孢子素刺激中性粒细胞产生巨噬细胞炎性蛋白-2(MIP-2)。P44/42MAPK和p38MAPK均参与MIP-2mRNA的稳定和MIP-2蛋白的翻译。(2)IL-5诱导的嗜酸性粒细胞存活不依赖p44/42MAPK。而炎症部位中性粒细胞的凋亡是由p38MAPK的持续激活所介导的。(3)星状孢子素刺激巨噬细胞可增加花生四烯酸的释放。花生四烯酸释放增加是由于胞浆磷脂酶A2被p44/42MAPK磷酸化所致。此外，在RAW264.7细胞中，thapsigargin诱导组氨酸脱羧酶和组胺的产生。组氨酸脱羧酶的转录也受p44/42MAPK的调控。(4)在肥大细胞中，p38MAPK部分参与了抗原诱导的IL-4的产生。(5)MAPKs不介导干扰素-γ诱导的细胞间黏附分子-1的表达。此外，我们还证实了类固醇抗炎药通过抑制MAPKs的激活来抑制巨噬细胞花生四烯酸的释放和组胺的产生。MAPK抑制剂对这些反应的抑制作用与类固醇抗炎药几乎相同。这些发现表明，MAPK是一种新型抗炎药物的开发靶点之一。