Lang K, Hatt H, Niggemann B, Zaenker K S, Entschladen F
Institute for Immunology, Witten/Herdecke University, Stockumer Strasse 10, 58448 Witten, Germany.
Scand J Immunol. 2003 Apr;57(4):350-61. doi: 10.1046/j.1365-3083.2003.01247.x.
Migration is a key function of stem cells during ontogenesis, of fibroblasts in wound healing and of immune cells in host defence. The signals that initiate migration are as important as signals that terminate migration, once the destination has been reached. We now show that formyl-methionyl-leucyl-phenylalanine (fMLP)-induced migration of neutrophils was inhibited by increasing concentrations of interleukin-8 (IL-8). IL-8 dose dependently increased the frequency and the duration of stop-periods, whereas the percentage of cells of a population that was locomotory active remained constant. The stop-signal delivered by IL-8 was intracellularly transduced by a dichotomic pathway: (i) the activation of the adenylyl cyclase leads to an increase of cytosolic cyclic adenosine monophosphate, which results in an activation of the sarcoplasmatic/endoplasmatic reticulum calcium ATPase pump and a calcium sequestration; (ii) the activation of the phospholipase Cbeta (PLCbeta) generates inositol-1,4,5-phosphate (IP3) and diacylglycerol (DAG), which results in IP3-mediated release of intracellularly stored calcium in the endoplasmatic reticulum and DAG-mediated activation of protein kinase C. Thus, we show for the first time that a chemokine, IL-8, in concert with fMLP, downregulates the neutrophil migration through the regulation of the intracellular calcium concentration via the adenylyl cyclase and the PLCbeta2.
迁移是干细胞在个体发育过程中、成纤维细胞在伤口愈合过程中以及免疫细胞在宿主防御过程中的关键功能。一旦到达目的地，启动迁移的信号与终止迁移的信号同样重要。我们现在发现，随着白细胞介素-8（IL-8）浓度的增加，甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）诱导的中性粒细胞迁移受到抑制。IL-8剂量依赖性地增加了停滞期的频率和持续时间，而活跃运动的细胞群体百分比保持不变。IL-8传递的停止信号通过一条二分途径在细胞内转导：（i）腺苷酸环化酶的激活导致胞质环磷酸腺苷增加，这导致肌浆网/内质网钙ATP酶泵激活和钙螯合；（ii）磷脂酶Cβ（PLCβ）的激活产生肌醇-1,4,5-三磷酸（IP3）和二酰甘油（DAG），这导致IP3介导的内质网中细胞内储存钙的释放以及DAG介导的蛋白激酶C激活。因此，我们首次表明，趋化因子IL-8与fMLP协同作用，通过腺苷酸环化酶和PLCβ2调节细胞内钙浓度来下调中性粒细胞迁移。
