title: IL-17 enhances IL-1beta-mediated CXCL-8 release from human airway smooth muscle cells.
abstract: Recent studies into the pathogenesis of airway disorders such as asthma have revealed a dynamic role for airway smooth muscle cells in the perpetuation of airway inflammation via secretion of cytokines and chemokines. In this study, we evaluated whether IL-17 could enhance IL-1beta-mediated CXCL-8 release from human airway smooth muscle cells (HASMC) and investigated the upstream and downstream signaling events regulating the induction of CXCL-8. CXCL-8 mRNA and protein induction were assessed by real-time RT-PCR and ELISA from primary HASMC cultures. HASMC transfected with site-mutated activator protein (AP)-1/NF-kappaB CXCL-8 promoter constructs were treated with selective p38, MEK1/2, and phosphatidylinositol 3-kinase (PI3K) inhibitors to determine the importance of MAPK and PI3K signaling pathways as well as AP-1 and NF-kappaB promoter binding sites. We demonstrate IL-17 induced and synergized with IL-1beta to upregulate CXCL-8 mRNA and protein levels. Erk1/2 and p38 modulated IL-17 and IL-1beta CXCL-8 promoter activity; however, IL-1beta also activated the PI3K pathway. The synergistic response mediating CXCL-8 promoter activity was dependent on both MAPK and PI3K signal transduction pathways and required the cooperation of AP-1 and NF-kappaB cis-acting elements upstream of the CXCL-8 gene. Collectively, our observations indicate MAPK and PI3K pathways regulate the synergy of IL-17 and IL-1beta to enhance CXCL-8 promoter activity, mRNA induction, and protein synthesis in HASMC via the cooperative activation of AP-1 and NF-kappaB trans-acting elements.
authors.affiliation: Department of Immunology, University of Manitoba, Manitoba, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dragon
authors.forename: Muhammad Shahidur
authors.initials: MS
authors.lastname: Rahman
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Abdelilah Soussi
authors.initials: AS
authors.lastname: Gounni
mesh_terms: D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C508606:CXCL8 protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases