IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts

J Allergy Clin Immunol. 2006 Mar;117(3):590-6. doi: 10.1016/j.jaci.2005.10.025. Epub 2006 Feb 8.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asthma / immunology*
  • Asthma / physiopathology
  • Biopsy
  • Bronchi / immunology
  • Bronchi / pathology
  • Cells, Cultured
  • Chemokine CCL11
  • Chemokine CCL5
  • Chemokines, CC / biosynthesis
  • Chemokines, CC / immunology
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / immunology
  • Chemotactic Factors, Eosinophil / biosynthesis
  • Chemotactic Factors, Eosinophil / immunology
  • Chemotaxis, Leukocyte
  • Cytokines / biosynthesis
  • Cytokines / immunology*
  • Cytokines / physiology
  • Eosinophil Major Basic Protein / biosynthesis
  • Eosinophil Major Basic Protein / immunology
  • Eosinophils / immunology*
  • Fibroblasts / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Inflammation
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / physiology*
  • Lung / immunology
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin-17
  • Transforming Growth Factor beta / physiology
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha / physiology
  • Up-Regulation

Substances

  • CCL11 protein, human
  • CCL5 protein, human
  • Chemokine CCL11
  • Chemokine CCL5
  • Chemokines, CC
  • Chemokines, CXC
  • Chemotactic Factors, Eosinophil
  • Cytokines
  • IL17RB protein, human
  • Interleukin-17
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Eosinophil Major Basic Protein