title: IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts.
abstract: BACKGROUND
  IL-17E is a new TH2 cytokine that promotes airway eosinophilia in mice. IL-17E proinflammatory activity has been proposed to involve induction of cytokine and chemokine production. Recruitment of inflammatory cells may be mediated by tissue-resident cells.
  
  
  OBJECTIVE
  This study aimed to evaluate whether fibroblasts represent a target of IL-17E for the production of eosinophil active mediators in the lung.
  
  
  METHODS
  Expression of IL-17B receptor (IL-17BR), a receptor for IL-17E, was evaluated by immunofluorescent staining, Western blot, and real-time PCR in human primary lung fibroblasts. Mediator production was analyzed by using real-time PCR and ELISA after stimulation of fibroblasts with IL-17E alone or in combination with TNF-alpha and TGF-beta1. Expression of IL-17E and of eosinophil major basic protein was evaluated by immunohistochemistry in bronchial biopsies from subjects with asthma.
  
  
  RESULTS
  Human primary lung fibroblasts constitutively expressed IL-17BR. IL-17BR mRNA levels were increased in cells stimulated with TNF-alpha and decreased with TGF-beta1. IL-17E slightly upregulated CC chemokine ligand (CCL)-5, CCL-11, GM-CSF, and CXC chemokine ligand (CXCL)-8 mRNA in fibroblasts. Moreover, IL-17E and TNF-alpha synergistically induced GM-CSF and CXCL-8 mRNA. IL-17E also potentiated the upregulation of CXCL-8 transcripts observed with TGF-beta1. In contrast, TGF-beta1 decreased IL-17E-induced CCL-11 mRNA. The capacity of IL-17E to enhance GM-CSF and CXCL-8 responses to TNF-alpha was accompanied by production and secretion of both proteins by lung fibroblasts. Finally, IL-17E was detected in asthma in eosinophil-infiltrated bronchial submucosa.
  
  
  CONCLUSIONS
  IL-17E may contribute to the induction and maintenance of eosinophilic inflammation in the airways by acting on lung fibroblasts. This study supports a role for IL-17E in asthma pathophysiology.
authors.affiliation: Meakins-Christie Laboratories, Department of Pathology and Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Séverine
authors.initials: S
authors.lastname: Létuvé
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lajoie-Kadoch
authors.forename: Séverine
authors.initials: S
authors.lastname: Audusseau
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fiset
authors.forename: Mara S
authors.initials: MS
authors.lastname: Ludwig
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
mesh_terms: D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D001706:Biopsy; D001980:Bronchi / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology; D002631:Chemotactic Factors, Eosinophil / Q000096:biosynthesis / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology; D047093:Eosinophil Major Basic Protein / Q000096:biosynthesis / Q000276:immunology; D004804:Eosinophils / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D053722:Receptors, Interleukin-17; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
chemical_list: C515456:CCL11 protein, human; C483024:CCL5 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019743:Chemokines, CXC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; C408922:IL17RB protein, human; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D047093:Eosinophil Major Basic Protein