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Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/
is essential for skin homeostasis and wound healing
Correspondence to Nguan Soon Tan: nstan{at}ntu.edu.sg
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 β/
(PPARβ/) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARβ/ 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 PPARβ/ 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 PPARβ/ regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARβ/, other epithelial–mesenchymal interactions may also be regulated in a similar manner.
Abbreviations used in this paper: AP-1, activation protein-1; ChIP, chromatin immunoprecipitation; EMSA, electrophoretic mobility shift assay; GMCSF, granulocyte macrophage colony-stimulating factor; icIL-1ra, intracellular IL-1ra; IL, interleukin; IL-1R, IL-1 receptor; IL-1ra, IL-1R antagonist; KGF, keratinocyte growth factor; OTC, organotypic skin culture; PCNA, proliferating cell nuclear antigen; PIGF, placental growth factor; PPAR, peroxisome proliferator–activated receptor; PPRE, peroxisome proliferator response elements; qPCR, quantitative real-time PCR; SDF-1, stromal-derived growth factor-1; sIL-1ra, secreted IL-1ra; TAK1, TGF-activated kinase 1; WT, wild type.
© 2009 Chong et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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