title: Induction of C-X-C chemokines, growth-related oncogene alpha expression, and epithelial cell-derived neutrophil-activating protein-78 by ML-1 (interleukin-17F) involves activation of Raf1-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 pathway.
abstract: Neutrophil recruitment into the airway typifies pulmonary inflammation and is regulated through chemokine network, 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 growth-related oncogene (GRO)alpha and epithelial cell-derived neutrophil activating protein (ENA)-78. The results showed first that ML-1 induces, in time- and dose-dependent manners, the gene and protein expressions for both chemokines in normal human bronchial epithelial cells and human umbilical vein endothelial cells. Furthermore, selective mitogen-activated protein kinase kinase (MEK) inhibitors 2'-amino-3'-methoxyflavone (PD98059), 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126), and Raf1 kinase inhibitor I partially inhibited Ml-1-induced 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) indol-3-yl)-3-(1-methylindol-3-yl) maleimide, acetate (Ro-31-7549), and a phosphatidylinositol 3-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), did not affect their production. Together, these data indicates a role for Raf1-MEK-extracellular signal-regulated kinase 1/2 pathway in ML-1 induced C-X-C chemokine expression, suggesting potential pharmacological targets for modulation.
authors.affiliation: Johns Hopkins University, Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224-6801, USA.
authors.forename: Mio
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Fumio
authors.initials: F
authors.lastname: Kokubu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsukura
authors.forename: Koushi
authors.initials: K
authors.lastname: Ieki
authors.forename: Miho
authors.initials: M
authors.lastname: Odaka
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
mesh_terms: D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC / Q000096:biosynthesis*; D002630:Chemotactic Factors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C475896:CXCL1 protein, Bos taurus; C486263:CXCL5 protein, human; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; C440021:IL17F protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D016209:Interleukin-8; D012333:RNA, Messenger; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1