title: Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin.
abstract: Abnormal epidermal proliferation and differentiation characterize the inflammatory skin disease psoriasis. Here we demonstrate that expression of PPARdelta mRNA and protein is markedly upregulated in psoriatic lesions and that lipoxygenase products accumulating in psoriatic lesions are potent activators of PPARdelta. The expression levels of NF-kappaB p50 and p65 were not significantly altered in lesional compared with nonlesional psoriatic skin. In the basal layer of normal epidermis both p50 and p65 were sequestered in the cytoplasm, whereas p50, but not p65, localized to nuclei in the suprabasal layers, and this distribution was maintained in lesional psoriatic skin. In normal human keratinocytes PPAR agonists neither impaired IL-1beta-induced translocation of p65 nor IL-1beta-induced NF-kappaB DNA binding. We show that PPARdelta physically interacts with the N-terminal Rel homology domain of p65. Irrespective of the presence of agonists none of the PPAR subtypes decreased p65-mediated transactivation in keratinocytes. In contrast p65, but not p50, was a potent repressor of PPAR-mediated transactivation. The p65-dependent repression of PPARdelta- but not PPARalpha- or PPARgamma-mediated transactivation was partially relieved by forced expression of the coactivators p300 or CBP. We suggest that deficient NF-kappaB activation in chronic psoriatic plaques permitting unabated PPARdelta-mediated transactivation contributes to the pathologic phenotype of psoriasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Majken
authors.initials: M
authors.lastname: Westergaard
authors.forename: Jeanette
authors.initials: J
authors.lastname: Henningsen
authors.forename: Claus
authors.initials: C
authors.lastname: Johansen
authors.forename: Sofie
authors.initials: S
authors.lastname: Rasmussen
authors.forename: Morten Lyhne
authors.initials: ML
authors.lastname: Svendsen
authors.forename: Uffe Birk
authors.initials: UB
authors.lastname: Jensen
authors.forename: Henrik Daa
authors.initials: HD
authors.lastname: Schrøder
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.forename: Knud
authors.initials: K
authors.lastname: Kragballe
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
mesh_terms: D018955:CD36 Antigens / Q000235:genetics; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000032:analysis* / Q000502:physiology; D011565:Psoriasis / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000235:genetics; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D015777:Eicosanoids; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors