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Eosinophil-Fibroblast Interactions in Fibrogenesis*: Eosinophils Induce Fibroblast Secretion of Interleukin–6 and Expression of Genes Involved in Extracellular Matrix Homeostasis

Sameer K. Mathur, MD, PhD; Bruce M. Espenshade; John Varga, MD; Steven J. Ackerman, PhD
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*From the Department of Biochemistry and Molecular Biology (Drs. Mathur and Ackerman, and Mr. Espenshade), and Section of Rheumatology (Dr. Varga), Department of Medicine, University of Illinois at Chicago, Chicago, IL.

Correspondence to: Steven J. Ackerman, PhD, Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, Mc536, A312 College of Medicine West, 1819 West Polk St, Chicago, IL 60612-7334; sackerma@vic.edu



Chest. 2001;120(1_suppl):S20. doi:10.1378/chest.120.1_suppl.S20
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Numerous observations, but few definitive studies, implicate eosinophils and their secretion products in pulmonary fibrosis and other forms of pathologic fibrosis. The role of the eosinophil, in terms of eosinophil signals that may induce or regulate fibroblast function, and the gene targets involved in these interactions, remain poorly defined. We previously reported1 that eosinophil granule major basic protein synergized with transforming growth factor-β1– or interleukin (IL)-1α–primed fibroblasts to upregulate expression of the IL-6 family of cytokines (IL-6, IL-11, leukemia inhibitory factor) at both the messenger RNA (mRNA) and protein levels. To extend these findings, we used a co-culture system of the human eosinophil-differentiated cell line, AML14.3D10, and either the human lung fibroblast cell line, CCL-202 (American Type Culture Collection), or primary foreskin fibroblasts, to address the nature of fibrogenic eosinophil-fibroblast interactions. We focused on IL-6, given the previous reports defining IL-6 as a key fibrogenic mediator. Co-culture of AML14.3D10 eosinophils with lung fibroblasts resulted in a large increase (up to 50-fold) in the secretion of fibroblast-derived IL-6. This increase was augmented approximately 50 to 100% by activating the AML14.3D10 eosinophils with IL-5 during the co-culture period. Reverse transcriptase-polymerase chain reaction analysis revealed that the increase in IL-6 secretion was associated with elevated levels of IL-6 mRNA in the fibroblasts. In addition, by gel mobility shift assays, we showed that co-culture increased DNA-binding activity for key IL-6 promoter elements nuclear factor-κB, CCAAT/enhancer binding protein (nuclear factor–IL-6), and AP1 in fibroblast nuclear extracts. To address the nature of the signaling between AML14.3D10 eosinophils and fibroblasts, a semipermeable barrier (“transwell”) culture system was used. The results revealed that induction of fibroblast IL-6 secretion is principally due to soluble mediators from the AML14.3D10 eosinophils. We also evaluated mRNA expression of genes involved in extracellular matrix homeostasis. Upon co-culture of AML14.3D10 eosinophils with primary foreskin fibroblasts, increased expression of plasminogen activator inhibitor type 1, fibronectin, and tissue inhibitor of metalloproteinase 1 mRNA was detected by reverse transcriptase-polymerase chain reaction. These findings show that co-culture of eosinophils and fibroblasts results in elevated expression of the genes for IL-6 and other fibrogenic products involved in extracellular matrix homeostasis. Eosinophil-fibroblast interactions are therefore capable of invoking a fibrogenic response.

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