Induction of C-X-C chemokines,growth-Related oncogene alpha expressionand epithelial cell-derived neutrophil-Activating Protein-78 by ML-1 (Interleukin-17F)Involves Activation of Raf1-Mitogen-Activated protein kinase kinase-Extracellular signal-regul

摘要

Neutrophil recruitment into hte airway typifies pulmonary inflammation and is regulated through chemokine networ,in which two C-X-C chemokines play a critical role.Airway epithelial cells and vein endothelial cells are major cell sources of chemokines.ML-1 (interleukin-17F)is a recently discovered cytokine and its function still remains elusive.In this report.we investigated the functional effect of ML-1 in the expression of growht-related oncogene (Gro)alpha and epitelial cell-derived neutrophil activation protein (ENA)-78.The results showed first that ML-1 inducess,in time- and dose-dependent manners,the gene and protein expressions for both chemokines in vormal human branchial epithelial cells and human umbilical vein endothelial cells.Furthermore,Selective mitogen-activated protein kinase kinase (mek)Inhibitors 2'-amino3'-methoxyflavone (PD98059),1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene (U0126),and Raf1 kinase inhibitor I partially inhibited M1-1-indkuced GROalpha and ENA-78 production.In contrast,the combination of PD98059 and Raf1 kinase inhibitor I completely abrogated the chemokine production,Whereas a protein kinase C inhibitor,2-(1-(3-aminopropyl)indol3-yl)-3-(1-methylindol-3-yl)maleimide,acetate (Ro-31-7549),and a phosphatidylinositol 3-kinease inhibitor,2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002),did not affect their production.Together,these data indicates role for Raf-1-MEK-extracellular signal-regulated kinase 1/2 pathway in ML-1 induced C-X-C chemokine expression,suggesting potental pharmacological targets for modulation.