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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 6, June, 2002 702-708

Concordant and Discordant Interleukin-1-Mediated Signaling in Lung Fibroblast Thy-1 Subpopulations

James S. Hagood, Anandit Mangalwadi, Benliu Guo, Mark W. MacEwen, Lorena Salazar, and Gerald M. Fuller

Departments of Pediatrics and Cell Biology, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama

Following lung injury or inflammation, fibroblasts mediate either restorative repair or disordered remodeling. Interleukin (IL)-1beta is a key mediator in the transition from injury/inflammation to tissue remodeling, in part through its regulation of platelet-derived growth factor alpha  receptor (PDGFalpha R). Based on prior demonstration of differential PDGFalpha R expression, we hypothesized that subpopulations of fibroblasts would have heterogeneous responses to IL-1. We report that IL-1beta significantly increases expression of PDGFalpha R in Thy-1-, but not Thy-1+ fibroblasts. Higher baseline expression of PDGFalpha R in Thy-1- fibroblasts is partially abrogated by IL-1 receptor antagonist. There are no differences in IL-1beta binding, as determined by flow cytometry, or in the presence of the type I IL-1 receptor (IL-1RtI) or its associated protein (IL-1RacP) by immunoblotting. IL-1beta induces DNA binding of both nuclear factor kappa B (NF-kappa B) and CAATT-enhancer binding protein (C/EBP), and activation of p38 mitogen-activated protein kinase in both subpopulations. However, IL-1beta -induced proliferation and expression of IL-6 are significantly higher in Thy-1- fibroblasts. Heterogeneous responses to IL-1beta despite equivalent presence of both proximal and distal signaling components indicates that parallel signaling pathways are activated selectively in Thy-1- cells, suggesting a prominent role for this subset in the transition from inflammation to lung remodeling.

Abbreviations: CAATT-enhancer binding protein, C/EBP; dithiothreitol, DTT; enhanced chemiluminescence, ECL; enzyme-linked immunosorbent assay, ELISA; electrophoretic mobility shift assay, EMSA; fetal bovine serum, FBS; fluorescein isothiocyanate, FITC; immunoglobulin G, IgG; interleukin, IL; IL-1 receptor-associated protein, IL-1RacP; type I IL-1 receptor, IL-1Rt1; nuclear factor kappa B, NF-kappa B; phosphate-buffered saline, PBS; PBS + 0.1% Tween 20, PBST; platelet-derived growth factor, PDGF; PDGF alpha  receptor, PDGFalpha R; phenylmethylsulfonyl fluoride, PMSF; sodium dodecyl sulfate, SDS; sodium dodecyl sulfate/polyacrylamide gel electrophoresis, SDS-PAGE; serum-free medium, SFM; tumor necrosis factor, TNF.




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