Concordant and discordant interleukin-1-mediated signaling in lung fibroblast thy-1 subpopulations.
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 (PDGFalphaR). Based on prior demonstration of differential PDGFalphaR expression, we hypothesized that subpopulations of fibroblasts would have heterogeneous responses to IL-1. We report that IL-1beta significantly increases expression of PDGFalphaR in Thy-1-, but not Thy-1+ fibroblasts. Higher baseline expression of PDGFalphaR 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 kappaB (NF-kappaB) 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.
Hagood
James S
JS
Department of Pediatrics, University of Alabama-Birmingham School of Medicine, 35294-0005, USA. jhagood@peds.uab.edu
Mangalwadi
Anandit
A
Guo
Benliu
B
MacEwen
Mark W
MW
Salazar
Lorena
L
Fuller
Gerald M
GM
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D007375:Interleukin-1 / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D007375:Interleukin-1; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D004247:DNA; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases