The autonomous and nonautonomous actions of PPARβ/δ. PPARβ/δ confers antiapoptotic properties to keratinocytes and potentiates their migration via AKT1 and Rho GTPases in a cell-autonomous manner (Di Poi et al., 2002; Tan et al., 2007). PPARβ/δ also influences keratinocyte differentiation in a yet unknown mechanism. PPARβ/δ regulates epidermal proliferation in a nonautonomous fashion via a paracrine mechanism. IL-1 constitutively produced by the adjacent keratinocytes activates c-Jun, an obligate partner of AP-1 transcription factor via TAK1, and consequently increases the production of several mitogenic factors. The expression of PPARβ/δ in the underlying fibroblasts attenuates this IL-1 signaling via the production of sIL-1ra. sIL-1ra has little affinity for IL-1R2, which is highly expressed in keratinocytes. Thus, sIL-1ra acts in an autocrine fashion onto the fibroblasts, which expressed the predominant functional IL-1R1. The binding of sIL-1ra to IL-1R1 modulates the IL-1–mediated signaling events and consequently decreases the production of several AP-1–mediated mitogenic factors. The mitogenic factors exert a reduced paracrine effect on the epithelial proliferation via their cognate receptors (R). Therefore, PPARβ/δ in the fibroblasts plays an important homeostatic role in maintaining epidermal homeostasis, the absence of PPARβ/δ resulting in significant epidermal proliferation.