Induction of granulocyte-macrophage colony-stimulating factor by a new cytokine, ML-1 (IL-17F), via Raf I-MEK-ERK pathway
Induction of granulocyte-macrophage colony-stimulating factor by a new cytokine, ML-1 (IL-17F), via Raf I-MEK-ERK pathway
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DOI：
10.1016/j.jaci.2004.03.047
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发表时间：
2004-08-01
影响因子：
14.2
通讯作者：
Huang, SK
中科院分区：
文献类型：
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作者：
Kawaguchi, M;Kokubu, F;Huang, SK
背景：IL-1(IL-17F)是一种新近发现的细胞因子，其功能尚不清楚。目的：研究ML-1在GM-CSF表达中的作用。方法：分别用RT-PCR和ELISA法检测正常人支气管上皮细胞(NHBE)在有或无多种激酶抑制剂或Raf1显性阴性突变体的情况下的基因和蛋白表达水平。结果：ML-1以时间和剂量依赖的方式诱导GM-CSF NHBE的基因和蛋白表达，并与Raf1和MAP激酶(MEK)的激活有关。选择性MEK抑制剂PD98059和U0126以及Raf1激酶抑制剂I显著抑制ML-1诱导的GM-CSF的产生。此外，过表达Raf1显性-负性突变体可抑制IL-17F诱导的GMCSF的表达。PD98059和Ranf1激酶抑制剂I可完全阻断GM-CSF的产生，而两种蛋白激酶C抑制剂Ro-31-7549和GF109203X以及磷脂酰肌醇3-激酶抑制剂LY294002则无抑制作用。结论：ML-1通过激活Raf1-MEK-细胞外信号调节激酶1/2途径诱导GM-CSF的表达。
Background: ML-1 (IL-17F) is a recently discovered cytokine, and its function remains elusive. GM-CSF is a crucial cytokine for the maturation of various cell types and regulates allergic airway inflammation.Objective: The functional effect of ML-1 in the expression of GM-CSF was investigated.Methods: The levels of gene and protein expression in normal human bronchial epithelial cells (NHBEs) in the presence or absence of various kinase inhibitors or, in some cases, of a Raf1 dominant-negative mutant were determined by RT-PCR and ELISA, respectively. Western blotting was performed to investigate kinase activation.Results: The results showed first that ML-1 induces, in a time-dependent and dose-dependent manner, the gene and protein expression for GM-CSF NHBEs, which are associated with activation of Raf1 and MAP kinase kinase (MEK) kinases. Selective MEK inhibitors, PD98059 and U0126, and Raf1 kinase inhibitor I significantly inhibited ML-1-induced GM-CSF production. Furthermore, overexpression of Raf1 dominant-negative mutants inhibited IL-17F-induced GMCSF expression. The combination of PD98059 and Ranf1 kinase inhibitor I completely blocked GM-CSF production, whereas 2 protein kinase C inhibitors, Ro-31-7549 and GF109203X, and a phosphatidylinositol 3-kinase inhibitor, LY294002, showed no inhibitory effect.Conclusion: These findings suggest that ML-1 induces GM-CSF expression through the activation of the Raf1-MEK-extracellular signal-regulated kinase 1/2 pathway.