Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/δ is essential for skin homeostasis and wound healing

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/δ (PPARβ/δ) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARβ/δ 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/δ 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/δ regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARβ/δ, other epithelial–mesenchymal interactions may also be regulated in a similar manner

Dynamics of nuclear receptor target gene regulation

Ligand-regulated nuclear receptors, such as estrogen receptors, glucocorticoid receptor, vitamin D receptor, and peroxisome proliferator-activated receptors, belong to the most widely studied and best understood transcription factors. Therefore, the dynamic nature of transcriptional regulation was observed first with different members of the nuclear receptor superfamily, but is now also extended to other transcription factors, such as nuclear factor κB. Dynamic and in part cyclical processes were observed on the level of translocation into the nucleus, association with genomic binding sites, exchange of co-regulators and chromatin modifiers, occurrence of chromatin marks, and activities of RNA polymerase II resulting in mRNA synthesis. In this review, we summarize recent findings on the dynamic regulation of nuclear receptor target genes in the chromatin context