Xiao Y Q, Minami K, Mue S, Ohuchi K
Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Eur J Pharmacol. 1998 Nov 6;360(2-3):195-204. doi: 10.1016/s0014-2999(98)00681-5.
Several types of kinase inhibitors were used to investigate the possible signaling pathways leading to the chemotaxis of rat peritoneal neutrophils toward macrophage inflammatory protein-2, cytokine-induced neutrophil chemoattractant-1, and platelet-activating factor. The chemotaxis and shape changes induced by each of these chemoattractants were strongly inhibited by a tyrosine kinase inhibitor (herbimycin A) and protein kinase C inhibitors (H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride) and calphostin C). The formation of phosphatidyl 3,4,5-triphosphate in chemoattractant-stimulated neutrophils was completely inhibited by 100 nM of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, whereas the chemotaxis toward each of these chemoattractants was partially inhibited (50% inhibition). The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK-1) inhibitor PD 98059 did not inhibit the neutrophil chemotaxis. These findings suggest that the activation of tyrosine kinase and protein kinase C strongly participates in neutrophil chemotaxis and that the activation of phosphatidylinositol 3-kinase is partially involved, but that the activation of mitogen-activated protein kinase is not involved in neutrophil chemotaxis. The cross-linking of the signaling pathways for chemotaxis toward each chemoattractant was also examined.
使用了几种类型的激酶抑制剂来研究可能导致大鼠腹膜中性粒细胞向巨噬细胞炎性蛋白-2、细胞因子诱导的中性粒细胞趋化因子-1和血小板活化因子趋化的信号通路。酪氨酸激酶抑制剂（赫曲霉素A）和蛋白激酶C抑制剂（H-7（1-(5-异喹啉磺酰基)-2-甲基哌嗪二盐酸盐）和钙磷蛋白C）强烈抑制了这些趋化因子各自诱导的趋化作用和形态变化。磷脂酰肌醇3激酶的抑制剂100 nM渥曼青霉素完全抑制了趋化因子刺激的中性粒细胞中磷脂酰3,4,5-三磷酸的形成，而对这些趋化因子各自的趋化作用则受到部分抑制（50%抑制）。丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK-1）抑制剂PD 98059不抑制中性粒细胞趋化作用。这些发现表明，酪氨酸激酶和蛋白激酶C的激活强烈参与中性粒细胞趋化作用，磷脂酰肌醇3激酶的激活部分参与，但丝裂原活化蛋白激酶的激活不参与中性粒细胞趋化作用。还研究了针对每种趋化因子的趋化信号通路的交联。
