title: Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: implications in fibrogenesis.
abstract: BACKGROUND
  Eosinophils are frequently associated with tissue remodeling and fibrosis in allergic and other diseases and animal models. Their close physical proximity to fibroblasts at sites of tissue remodeling strongly implicates them in fibrogenesis, including subepithelial fibrosis and airway remodeling characteristic of asthma.
  
  
  OBJECTIVE
  To identify the mediators and characterize the mechanisms underlying the fibrogenic activities of eosinophils.
  
  
  METHODS
  A coculture system of blood eosinophils or eosinophil cell lines with normal fibroblasts was used to assess their ability to induce a fibrogenic fibroblast phenotype, including IL-6 secretion and mRNA expression, and induction of genes involved in extracellular matrix production and homeostasis. The mediators of these responses were identified by using transwell barrier cocultures, eosinophil-conditioned media, and cytokine-specific antibody neutralization.
  
  
  RESULTS
  Eosinophil-fibroblast coculture induced potent fibroblast IL-6 secretion and mRNA expression, responses further enhanced by IL-5. The soluble nature of the eosinophil-derived mediators was demonstrated by using eosinophil-fibroblast coculture in the presence of permeable transwell barriers, and fibroblast culture in eosinophil-conditioned media, indicating that cell contact was not required. Induction of fibroblast IL-6 expression was accompanied by increased expression of fibronectin and the extracellular matrix regulatory genes plasminogen activator inhibitor 1 and tissue inhibitor of metalloproteinase 1. Antibody neutralization identified the principal eosinophil-derived mediator of fibroblast IL-6 expression as IL-1beta (>60%), with lesser contributions from IL-1alpha, IL-4, and TGF-beta (10% to 20%).
  
  
  CONCLUSIONS
  Eosinophils express at least 2 potent mediators (IL-1beta and TGF-beta) that induce a fibrogenic fibroblast phenotype, strongly supporting a role for the eosinophil in the dysregulation of extracellular matrix homeostasis and consequent tissue remodeling and fibrosis in eosinophil-associated diseases.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Ignatius
authors.initials: I
authors.lastname: Gomes
authors.forename: Sameer K
authors.initials: SK
authors.lastname: Mathur
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Espenshade
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Mori
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ackerman
mesh_terms: D002450:Cell Communication; D018920:Coculture Techniques; D004804:Eosinophils / Q000276:immunology* / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology* / Q000502:physiology; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta