Chong et al. found that PPARβ/δ-deficient fibroblasts made wild type keratinocytes hyperproliferative in OTCs by secreting extra doses of several growth factors. The fibroblasts were stimulated to produce these growth factors by keratinocyte-released cytokine IL-1 - underscoring the reciprocity between the two cell types. Blocking either the IL-1 signal or any of the growth factors released by the fibroblasts returned the OTCs to normal.
So why do fibroblasts lacking PPARβ/δ send out more growth factors in response to IL-1? The authors discovered that PPARβ/δ stimulates the production of sIL-1ra, a protein that inhibits IL-1 signaling by competing for the IL-1 receptor. Normally, this would decrease the IL-1 signal received by fibroblasts and therefore reduce the growth factor signals sent back to the keratinocytes. But in PPARβ/δ's absence, fibroblasts keep stimulating keratinocyte division. Similarly, PPARβ/δ knockout mice expressed less sIL-1ra after wounding and produced more growth factors that stimulate the epidermis. "Proliferation is important in early stages of wound healing," explains Tan. "But excessive proliferation isn't good: you can end up with hypertrophic scarring."
This may also be critical to prevent tumor development. Contradictory reports exist on whether PPARβ/δ promotes or inhibits epithelial cancers (4-6). Tan's group has already found that fibroblasts lacking the protein can increase the proliferation of squamous carcinoma cells; they now plan to investigate PPARβ/δ's expression in tumor-associated fibroblasts. "Fibroblasts often play important roles by communicating with
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