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

TY - JOUR

T1 - PPAR delta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor

AU - Romanowska, Malgorzata

AU - Al Yacoub, Nadya

AU - Seidel, Henrik

AU - Donandt, Susanne

AU - Gerken, Hannah

AU - Phillip, Sandra

AU - Haritonova, Nathalie

AU - Artuc, Metin

AU - Schweiger, Susann

AU - Sterry, Wolfram

AU - Foerster, John

PY - 2008/1

Y1 - 2008/1

N2 - 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.

AB - 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.

KW - Psoriasis

KW - Epidermal-keratinocytes

KW - Intercellular signaling peptides and proteins

KW - PPAR delta

KW - Gene expression profiling

KW - Gene expression regulation

KW - Transcription factor AP-1

KW - NF-kappa B

KW - Cell proliferation

U2 - 10.1038/sj.jid.5700943

DO - 10.1038/sj.jid.5700943

M3 - Article

C2 - 17637826

SN - 0022-202X

VL - 128

SP - 110

EP - 124

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 1

ER -