Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: Implications in fibrogenesis - 18/08/11
Reprint requests: Steven J. Ackerman, PhD, Department of Biochemistry and Molecular Genetics, MC669, University of Illinois at Chicago, Molecular Biology Research Building, Rm 2074, 900 S Ashland Ave, Chicago, IL 60607.Chicago, Ill, Madison, Wis, and South Bend, Ind
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-1β (>60%), with lesser contributions from IL-1⍺, IL-4, and TGF-β (10% to 20%).
Conclusion |
Eosinophils express at least 2 potent mediators (IL-1β and TGF-β) 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.
Le texte complet de cet article est disponible en PDF.Key words : Eosinophil, fibrosis, IL-1⍺, IL-1β, IL-5, IL-6, TGF-β, fibronectin, PAI-1, TIMP-1
Abbreviations used : ECM, ECP, EDN, MBP, NF-κB, PAI-1, TIMP
Plan
| Supported in part by National Institutes of Health grants AI25230 (Dr Ackerman) and AR42309 (Dr Varga), and a grant from the Eosinophil Myalgia Syndrome Foundation (Showadenko Ltd; Dr Varga and Dr Ackerman). This work was also supported in part by the General Clinical Research Center at the University of Illinois at Chicago, which is funded by National Institutes of Health grant M01-RR-13987. |
Vol 116 - N° 4
P. 796-804 - octobre 2005 Retour au numéro
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