transforming-growth-factor-alpha and Dermatitis

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA+UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50μM resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR.

Topics: Basic Helix-Loop-Helix Transcription Factors; Dermatitis; Flavonoids; Gene Expression; Humans; Immunoblotting; Inflammation; Interferon-gamma; Keratinocytes; Lipopolysaccharides; NF-kappa B; Phenols; Polyphenols; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Transforming Growth Factor alpha; Ultraviolet Rays

Prion diseases are transmissible spongiform encephalopathies of humans and animals characterized by the accumulation of a proteinase-resistant isoform of the cellular prion-related protein (PrPc) within the central nervous system. In the present report we demonstrate for the first time the presence of PrPc on squamous epithelia of normal and diseased human skin and show that inflammatory cytokines regulate PrPc expression in cultured human keratinocytes (KCs). By immunohistochemistry, only little expression of PrPc, which was mainly confined to KCs, was detected in normal skin. In contrast, in inflammatory skin diseases including psoriasis and contact dermatitis, PrPc was strongly present on both KCs and infiltrating mononuclear cells. Strong PrPc expression was also observed in squamous cell carcinomas and viral warts whereas basal cell carcinomas were mostly negative. In mucous membranes of the upper digestive tract and the genital region, distinct PrPc expression by basal squamous epithelial cells was a constant feature. In tissue culture, primary KCs constitutively expressed PrPc mRNA and protein. Exposure of these cells to transforming growth factor (TGF)-alpha or interferon (IFN)-gamma led to an increase of PrPc protein expression. The presence of PrPc on epithelial cells of skin and mucous membranes suggests that these cells represent possible first targets for peripheral infection with prions.

Topics: Blotting, Western; Cells, Cultured; Dermatitis; Flow Cytometry; Humans; Interferon-gamma; Keratinocytes; Melanoma; Mucous Membrane; PrPC Proteins; Transforming Growth Factor alpha; Tumor Cells, Cultured; Up-Regulation