Interleukin-8 regulation of the Ras/Raf/mitogen-activated protein kinase pathway in human neutrophils
Interleukin-8 regulation of the Ras/Raf/mitogen-activated protein kinase pathway in human neutrophils
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DOI：
10.1074/jbc.271.5.2832
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发表时间：
1996-02-02
影响因子：
4.8
通讯作者：
Johnson, GL
中科院分区：
文献类型：
--
作者：
Knall, C;Young, S;Johnson, GL
白细胞介素-8（IL-8）是趋化因子CXC亚家族的原型成员，在中性粒细胞中诱导趋化性、呼吸爆发、颗粒释放和增加的细胞粘附。IL-8受体是与包括G（i）和G（16）的特异性异源三聚体G蛋白偶联的七跨膜受体。IL-8对其在中性粒细胞上的受体的刺激激活Ras GTP负载和丝裂原活化蛋白激酶（MAPK）途径，包括Raf-1和B-Raf。MAPK途径的IL-8刺激的性质不同于对于诸如C5 a的化学引诱物所观察到的那些。尽管IL-8和C5 a的Ras GTP负载相似，但Raf-1和B-Raf的最大活化分别为IL-8的约2倍和3-7倍，比对C5 a观察到的小。Raf-1的激活是快速的，但短暂的，返回到接近基础水平的10分钟。B-Raf激活是在发病较慢，并没有返回到基础水平近30分钟，IL-8激活MAPK遵循一个时间过程，表明参与Raf-1和B-Raf。令人惊讶的是，低浓度的渥曼青霉素抑制Raf-1、B-Raf和MAPK对IL-8和C5 a的应答活化，这证明了磷脂酰肌醇3-激酶在人嗜中性粒细胞中G蛋白偶联受体系统中Raf激酶的活化中的作用。此外，渥曼青霉素抑制IL-8刺激的颗粒释放和中性粒细胞粘附。这些发现证明了磷脂酰肌醇3-激酶对Raf激酶、MAPK途径和特定中性粒细胞功能的控制。
Interleukin-8 (IL-8), the prototypic member of the CXC subfamily of chemokines, induces in neutrophils chemotaxis, the respiratory burst, granule release, and increased cell adhesion, The IL-8 receptor is a seven-transmembrane spanning receptor coupled to specific heterotrimeric G proteins including G(i) and G(16). IL-8 stimulation of its receptor on neutrophils activates Ras GTP loading and the mitogen-activated protein kinase (MAPK) pathway including Raf-1 and B-Raf. The properties of IL-8 stimulation of the MAPK pathway differ from those observed for chemoattractants such as C5a. Even though Ras GTP loading is similar for IL-8 and C5a, the maximal activation of Raf-1 and B-Raf is approximately 2-fold and 3-7-fold, respectively, less for IL-8 than that observed for C5a. Raf-1 activation is rapid but transient, returning to near basal levels by 10 min. B-Raf activation is slower in onset and does not return to basal levels for nearly 30 min, IL-8 activation of MAPK follows a time course suggesting an involvement of both Raf-1 and B-Raf. Surprisingly, wortmannin, at low concentrations, inhibits Raf-1, B-Raf, and MAPK activation in response to IL-8 and C5a demonstrating a role for phosphatidylinositol 3-kinase in the activation of Raf kinases in G protein-coupled receptor systems in human neutrophils. Furthermore, wortmannin inhibits IL-8 stimulated granule release and neutrophil adherence, These findings demonstrate the control of Raf kinases, the MAPK pathway and specific neutrophil functions by phosphatidylinositol 3-kinase enzymes.