Abstract
Skin morphogenesis, maintenance, and healing after wounding require complex epithelial-mesenchymal interactions. In this study, we show that for skin homeostasis, interleukin-1 (IL-1) produced by keratinocytes activates peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARbeta/delta stimulates production of the secreted IL-1 receptor antagonist, which leads to an autocrine decrease in IL-1 signaling pathways and consequently decreases production of secreted mitogenic factors by the fibroblasts. This fibroblast PPARbeta/delta regulation of the IL-1 signaling is required for proper wound healing and can regulate tumor as well as normal human keratinocyte cell proliferation. Together, these findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated via PPARbeta/delta regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARbeta/delta, other epithelial-mesenchymal interactions may also be regulated in a similar manner.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autocrine Communication
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Cell Differentiation
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Cell Proliferation
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Cells, Cultured
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Cytokines / metabolism
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Epithelial Cells / enzymology
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Epithelial Cells / immunology
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Epithelial Cells / metabolism*
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Fibroblasts / enzymology
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Fibroblasts / immunology
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Fibroblasts / metabolism*
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Gene Knockdown Techniques
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Homeostasis
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin 1 Receptor Antagonist Protein / metabolism
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Interleukin-1 / genetics
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Interleukin-1 / metabolism*
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Interleukin-1alpha / metabolism
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Interleukin-1beta / metabolism
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Knockout
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Organ Culture Techniques
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PPAR delta / deficiency
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PPAR delta / genetics
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PPAR delta / metabolism*
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PPAR-beta / deficiency
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PPAR-beta / genetics
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PPAR-beta / metabolism*
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Paracrine Communication
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Promoter Regions, Genetic
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RNA Interference
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Signal Transduction*
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Skin / enzymology
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Skin / immunology
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Skin / metabolism*
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation
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Wound Healing*
Substances
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Cytokines
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Intercellular Signaling Peptides and Proteins
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1
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Interleukin-1alpha
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Interleukin-1beta
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PPAR delta
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PPAR-beta
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Transcription Factor AP-1
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7