Abstract
Excessive accumulation of collagen contributes to the fibrotic process. Several experimental studies have shown that IFN-gamma is effective in preventing fibrogenesis. IL-18, originally identified as an IFN-gamma-inducing factor, is a key mediator of inflammation and host defense responses. In this study, we investigated the regulatory effect of IL-18 on the expression of type I and III collagen genes in dermal fibroblasts. The exposure of human dermal fibroblasts (HDFs) to IL-18 resulted in a reduction of collagen gene expression and production. Also, IL-18 inhibited the fibrogenic cytokine transforming growth factor (TGF)-beta-induced collagen gene expression. Next, to determine the molecular mechanism involved in this regulation, we showed that IL-18-regulated collagen expression was blocked by small interfering RNA (siRNA)-mediated Ets-1 knockdown. Furthermore, we showed that IL-18 induced phosphorylation of extracellular signal-regulated kinase (ERK) within 10 minutes and that the ERK inhibitor PD98059 blocked the inhibitory effect of IL-18. IL-18 also inhibited the production of collagen in systemic sclerosis (SSc) dermal fibroblasts. Our data indicate that IL-18 downregulates collagen production in HDF directly via Ets-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Collagen / genetics
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Collagen / metabolism
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Collagen Type I / genetics
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Collagen Type I / metabolism*
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Collagen Type I, alpha 1 Chain
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Collagen Type III / genetics
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Collagen Type III / metabolism
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Dermis / cytology*
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Flavonoids / pharmacology
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Gene Expression / drug effects
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Gene Expression / physiology
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Humans
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Interleukin-18 / metabolism*
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Interleukin-18 / pharmacology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Promoter Regions, Genetic / physiology
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / metabolism
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RNA, Small Interfering
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Scleroderma, Systemic / metabolism*
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Scleroderma, Systemic / physiopathology
Substances
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COL3A1 protein, human
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Collagen Type I
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Collagen Type I, alpha 1 Chain
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Collagen Type III
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ETS1 protein, human
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Enzyme Inhibitors
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Flavonoids
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Interleukin-18
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Proto-Oncogene Protein c-ets-1
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RNA, Small Interfering
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Collagen
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Extracellular Signal-Regulated MAP Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one