External signals stimulate PPARβ expression and cell differentiation in primary mouse keratinocyte cultures. (A) Apoptosis-derived CM and necrosis-derived CM induce keratinocyte differentiation. Primary keratinocytes from wild-type (first, third, and fifth panels) or from PPARβ−/− mice (second and fourth panels) were exposed at time 0 (usually after two or three passages) to conditioned medium (CM) from mixed leukocyte reactions (MLR), prepared either with apoptotic fibroblasts (first and second panels) or with necrotic cells (third, fourth, and fifth panels). Keratinocytes were lysed after different times of exposure to CM as indicated, and the expression of PPARβ was evaluated by RPA. The expression of involucrin (INV), transglutaminase I (TgaseI), was used as markers of keratinocyte differentiation. The expression of keratin (K) K6, K10, and K17 reflects different pathways of keratinocyte differentiation. Cyclin A (Cyc A) expression indicated the status of the cell with respect to cell cycle. In the fifth panel, the necrosis-derived CM was precleared of TNF-α. (B) The major pro-inflammatory mediators TNF-α, IFN-γ, and TPA up-regulate PPARβ expression. Primary keratinocytes from wild-type (first, third, and fifth panels) or from PPARβ−/− mice (second, fourth, and sixth panels) were cultured in KSFM and exposed at time 0 to TNF-α 5 ng/ml (first and second panels) IFN-γ 5 ng/ml (third and fourth panels). or TPA 20 ng/ml (fifth and sixth panels). In all three treatments, the expression of all differentiation markers is strongly reduced and delayed in PPARβ−/− cells.