Critical roles of PPARβ/δ in keratinocyte response to inflammation

Nguan Soon Tan; Liliane Michalik; Noa Noy; Rubina Yasmin; Corinne Pacot; Manuel Heim; Beat Flühmann; Beatrice Desvergne; Walter Wahli

doi:10.1101/gad.207501

Critical roles of PPARβ/δ in keratinocyte response to inflammation

¹Institut de Biologie Animale, Université de Lausanne, CH-1015 Lausanne, Switzerland; ²F. Hoffmann-La Roche Ltd, Vitamins and Fine Chemicals Division, Human Nutrition and Health, 4070 Basel, Switzerland

Abstract

The immediate response to skin injury is the release of inflammatory signals. It is shown here, by use of cultures of primary keratinocytes from wild-type and PPARβ/δ^−/− mice, that such signals including TNF-α and IFN-γ, induce keratinocyte differentiation. This cytokine-dependent cell differentiation pathway requires up-regulation of the PPARβ/δ gene via the stress-associated kinase cascade, which targets an AP-1 site in thePPARβ/δ promoter. In addition, the pro-inflammatory cytokines also initiate the production of endogenous PPARβ/δ ligands, which are essential for PPARβ/δ activation and action. Activated PPARβ/δ regulates the expression of genes associated with apoptosis resulting in an increased resistance of cultured keratinocytes to cell death. This effect is also observed in vivo during wound healing after an injury, as shown in dorsal skin of PPARβ/δ^+/+ and PPARβ/δ^+/− mice.

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Footnotes

Present addresses: ³Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; ⁴Laboratoire de Biologie Comparée, UMR-CNRS 6023, Université Blaise Pascal, 63117 Aubière Cedex, France.
↵5 Corresponding author.
E-MAIL walter.wahli{at}iba.unil.ch; FAX 41-21-692-4115.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.207501.
- Received May 7, 2001.
- Accepted October 25, 2001.
Cold Spring Harbor Laboratory Press