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

在本研究中，MAP激酶在各种炎症细胞（中性粒细胞，嗜酸性粒细胞，巨噬细胞，肥大细胞，上皮细胞）的反应中的作用进行了分析。结果表明：（1）星形孢菌素刺激中性粒细胞可诱导巨噬细胞炎性蛋白-2（MIP-2）的产生。p44/42 MAPK和p38 MAPK均参与MIP-2 mRNA的稳定和MIP-2蛋白的翻译。(2)白细胞介素-5诱导的嗜酸性粒细胞的存活不依赖于p44/42 MAPK。相反，炎症部位浸润的中性粒细胞的凋亡是由p38 MAPK的持续激活介导的。(3)用星形孢菌素刺激巨噬细胞增加花生四烯酸的释放。花生四烯酸释放的增加是由于p44/42 MAPK磷酸化胞浆磷脂酶A_2所致。此外，在RAW264.7细胞中，毒胡萝卜素诱导组氨酸脱羧酶和组胺产生的诱导。组氨酸脱羧酶的转录也受p44/42 MAPK的调控。(4)在肥大细胞中，p38 MAPK部分参与抗原诱导的IL-4产生。(5)MAPKs不介导IFN-γ诱导的上皮细胞ICAM-1表达。此外，我们证明类固醇抗炎药通过抑制MAPKs的活化来抑制巨噬细胞中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是开发新的抗炎药物的靶点之一。

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.