PPAR delta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor

Malgorzata Romanowska, Nadya Al Yacoub, Henrik Seidel, Susanne Donandt, Hannah Gerken, Sandra Phillip, Nathalie Haritonova, Metin Artuc, Susann Schweiger, Wolfram Sterry, John Foerster

    Research output: Contribution to journalArticle

    72 Citations (Scopus)

    Abstract

    Psoriasis is a common skin disease involving keratinocyte proliferation and altered differentiation, as well as T-cell activation. Here, we show that altered gene transcription in psoriatic skin lesions is highly reproducible between independent data sets. Analysis of gene expression confirmed dysregulation in all expected functional categories, such as IFN signaling and keratinocyte differentiation, and allowed molecular fingerprinting of a previously characterized dendritic cell subset associated with psoriasis tumor necrosis factor alpha (TNF-alpha)- and inducible nitric oxide synthase (iNOS)-producing CD11b(INT) DC (Tip-DC). Unexpectedly, a large group of dysregulated transcripts was related to fatty acid signaling and adipocyte differentiation, exhibiting a pattern consistent with the activation of peroxisome proliferator-activated receptor delta (PPAR delta). PPAR delta itself was strongly induced in psoriasis in vivo. In primary keratinocytes, PPAR delta was induced by the transcription factor activator protein 1, in particular by junB, but not by canonical WNT signaling, in contrast to its regulation in colon carcinoma cells. Activation of PPAR delta enhanced proliferation of keratinocytes, while this was inhibited by knockdown of PPAR delta. Finally, heparin-binding EGF-like growth factor (HB-EGF), known to induce epidermal hyperplasia and itself overexpressed in psoriasis, was identified as a direct target gene of PPAR delta. The present data suggest that activation of PPAR delta is a major event in psoriasis, contributing to the hyperproliferative phenotype by induction of HB-EGF.

    Original languageEnglish
    Pages (from-to)110-124
    Number of pages15
    JournalJournal of Investigative Dermatology
    Volume128
    Issue number1
    DOIs
    Publication statusPublished - Jan 2008

    Keywords

    • Psoriasis
    • Epidermal-keratinocytes
    • Intercellular signaling peptides and proteins
    • PPAR delta
    • Gene expression profiling
    • Gene expression regulation
    • Transcription factor AP-1
    • NF-kappa B
    • Cell proliferation

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