Expression and localization of peroxisome proliferator-activated receptors and nuclear factor kappaB in normal and lesional psoriatic skin.
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.
Westergaard
Majken
M
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Henningsen
Jeanette
J
Johansen
Claus
C
Rasmussen
Sofie
S
Svendsen
Morten Lyhne
ML
Jensen
Uffe Birk
UB
Schrøder
Henrik Daa
HD
Staels
Bart
B
Iversen
Lars
L
Bolund
Lars
L
Kragballe
Knud
K
Kristiansen
Karsten
K
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
D018955:CD36 Antigens; D015777:Eicosanoids; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors