Expression and Localization of Peroxisome Proliferator-Activated Receptors and Nuclear Factor κB 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.

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

“…In addition, PPARb/y-deficient mice displayed an exaggerated hyperproliferative response to TPA, suggesting that this receptor is critical for attenuating epidermal proliferation (30,52). It was suggested that in the hyperproliferative epidermis of psoriatic skin, PPARb/y overexpression mediates keratinocyte proliferation via NF-kB (44). Together, these results indicate that the absence of PPARb/y leads to increased keratinocyte proliferation and that under some experimental conditions PPARb/y activators inhibit keratinocyte proliferation.…”

“…Alterations in PPAR expression in psoriasis (32,44) and the anti-inflammatory and prodifferentiating effects of PPAR and LXR activation on the epidermis described above prompted clinical trials exploring the efficacy and safety of PPAR-targeted therapy. A striking improvement of skin lesions had initially been documented in patients with psoriasis treated with the oral PPARg activator troglitazone (9,113).…”

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

“…Several nuclear hormone liposensors, including peroxisome proliferator-activated receptor a (PPARa), PPARb/D, PPARg, and LXR-a and -b, are expressed in keratinocytes (167)(168)(169). Studies by our laboratory and others have shown that activation of PPARs and LXRs has major effects on epidermal/keratinocyte function.…”

The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

“…Sixteen hours later the cells were lysed and samples read on a luminometer. Dose curves were plotted to determine the IC 50 for the blocking activity of the 5C9, 1B4, and 7E9 Abs.…”