title: AP1-dependent repression of TGFα-mediated MMP9 upregulation by PPARδ agonists in keratinocytes.
abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that function mainly in the regulation of glucose and lipid homeostasis. PPAR agonists have been shown to control inflammation by inhibition of distinct proinflammatory genes. Aberrant activation of the epidermal growth factor receptor and/or overexpression of its ligand, transforming growth factor-α (TGFα), are key features of both neoplastic and inflammatory hyperproliferative epithelia. Matrix metalloproteinase 9 (MMP9) belongs to the set of genes that are effectively induced by TGFα in keratinocytes. Induction of MMP9 expression is strongly linked to regenerative skin repair mechanisms, inflammatory skin diseases and tumor metastasis. We explored whether the known anti-inflammatory effects of PPARδ ligands involve inhibiting the TGFα-mediated upregulation of MMP9. The PPARδ agonists potently inhibited TGFα-induced MMP9 expression in human keratinocytes. This inhibition was observed at both the protein and mRNA levels. Transcriptional activation studies with deletion constructs of a reporter gene revealed that PPARδ agonists mediate their inhibitory effects via an AP1-binding site. Electromobility shift assay analysis indicated that MMP9 gene expression is inhibited by repressing site-dependent DNA binding and transactivation by c-fos. In conclusion, our data provide the first evidence that MMP9 expression induced by TGFα is a valid target of PPARδ ligands in keratinocytes.
authors.affiliation: Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. markus.meissner@kgu.de
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
authors.forename: Barbara
authors.initials: B
authors.lastname: Berlinski
authors.forename: Monika
authors.initials: M
authors.lastname: Doll
authors.forename: Igor
authors.initials: I
authors.lastname: Hrgovic
authors.forename: Vesselina
authors.initials: V
authors.lastname: Laubach
authors.forename: Gabi
authors.initials: G
authors.lastname: Reichenbach
authors.forename: Stefan
authors.initials: S
authors.lastname: Kippenberger
authors.forename: Jens
authors.initials: J
authors.lastname: Gille
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists*; D010642:Phenoxyacetates / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; C425931:GW 501516; D047494:PPAR delta; D010642:Phenoxyacetates; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D013844:Thiazoles; D018808:Transcription Factor AP-1; D016211:Transforming Growth Factor alpha; D020780:Matrix Metalloproteinase 9