title: IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways.
abstract: Recently, IL-17A has been shown to be expressed in higher levels in respiratory secretions from asthmatics and correlated with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanisms remain unknown. In this study, we investigated the molecular mechanisms involved in IL-17A-mediated CC chemokine (eotaxin-1/CCL11) production from human airway smooth muscle (ASM) cells. We found that incubation of human ASM cells with rIL-17A resulted in a significant increase of eotaxin-1/CCL11 release from ASM cells that was reduced by neutralizing anti-IL-17A mAb. Moreover, IL-17A significantly induced eotaxin-1/CCL11 release and mRNA expression, an effect that was abrogated with cycloheximide and actinomycin D treatment. Furthermore, transfection studies using a luciferase-driven reporter construct containing eotaxin-1/CCL11 proximal promoter showed that IL-17A induced eotaxin-1/CCL11 at the transcriptional level. IL-17A also enhanced significantly IL-1beta-mediated eotaxin-1/CCL11 mRNA, protein release, and promoter activity in ASM cells. Primary human ASM cells pretreated with inhibitors of MAPK p38, p42/p44 ERK, JNK, or JAK but not PI3K, showed a significant decrease in eotaxin-1/CCL11 release upon IL-17A treatment. In addition, IL-17A mediated rapid phosphorylation of MAPK (p38, JNK, and p42/44 ERK) and STAT-3 but not STAT-6 or STAT-5 in ASM cells. Taken together, our data provide the first evidence of IL-17A-induced eotaxin-1/CCL11 expression in ASM cells via MAPK (p38, p42/p44 ERK, JNK) signaling pathways. Our results raise the possibility that IL-17A may play a role in allergic asthma by inducing eotaxin-1/CCL11 production.
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Muhammad Shahidur
authors.initials: MS
authors.lastname: Rahman
authors.forename: Akira
authors.initials: A
authors.lastname: Yamasaki
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Lianyu
authors.initials: L
authors.lastname: Shan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Abdelilah Soussi
authors.initials: AS
authors.lastname: Gounni
mesh_terms: D001249:Asthma / Q000201:enzymology / Q000276:immunology; D001980:Bronchi / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000276:immunology*; D014132:Trachea / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; C508717:IL17A protein, human; D020381:Interleukin-17; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases