Abstract
Immune activation of fibrosis likely has a crucial role in the pathogenesis of systemic sclerosis (SSc). The aim of this study was to better understand the innate immune regulation and associated IFN- and transforming growth factor-β (TGFβ)-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo, we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes is increased in SSc skin and SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. Of the TLRs ligands tested, the TLR3 ligand, polyinosinic/polycytidylic acid (Poly(I:C)), most highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model, type I IFNs had no apparent role in regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, which is potentially mediated by TLR3 or other innate immune receptors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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Cells, Cultured
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Dermatitis / genetics
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Dermatitis / immunology*
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Dermatitis / pathology
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Dermis / immunology
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Dermis / pathology
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Disease Models, Animal
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / immunology
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GTP-Binding Proteins / metabolism
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Gene Expression / immunology
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Humans
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Interferon Type I / immunology*
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Interferon Type I / metabolism
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Lupus Erythematosus, Cutaneous / genetics
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Lupus Erythematosus, Cutaneous / immunology
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Lupus Erythematosus, Cutaneous / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Myxovirus Resistance Proteins
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Poly I-C / metabolism
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Poly I-C / pharmacology*
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Scleroderma, Systemic / genetics
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Scleroderma, Systemic / immunology*
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Scleroderma, Systemic / pathology
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Toll-Like Receptor 3 / agonists*
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Toll-Like Receptor 3 / immunology
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Toll-Like Receptor 3 / metabolism
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Transforming Growth Factor beta / immunology*
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Transforming Growth Factor beta / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Interferon Type I
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Myxovirus Resistance Proteins
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TICAM-1 protein, mouse
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TLR3 protein, mouse
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Toll-Like Receptor 3
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Transforming Growth Factor beta
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Interferon-gamma
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GTP-Binding Proteins
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Poly I-C