involucrin and ciglitazone

Therapeutic options for atopic dermatitis mostly address the symptoms but causal therapies are still missing. Peroxisome proliferator activated receptor (PPAR) agonists exert beneficial effects in patients suffering this disease, whereas the stimulation of PPARα and γ seemed most promising.. To elucidate the effects of the PPARα specific agonist WY14643, the PPARγ agonist ciglitazone, and the dual PPARα+γ agonist docosahexaenoic acid (DHA) on the homeostasis and barrier function of filaggrin deficient skin.. The effects of the PPAR agonists on skin differentiation were evaluated via qPCR, Western blot, histological or immunofluorescence staining. Skin lipid organization was determined by ATR-FTIR and lipid composition was analyzed by HPTLC. Ultimately, the skin barrier function was assessed by skin absorption studies using the radioactively labeled compound testosterone.. Significant upregulation of filaggrin after DHA and WY14643 supplementation, but no effect of ciglitazone, on protein and mRNA level was detected. DHA and WY14643, but not ciglitazone, normalized the molar ratio of the main skin barrier lipids to 1:1:1 (free fatty acids:ceramides:cholesterol). Furthermore, DHA and WY14643 supplementation normalized the skin lipid profile in filaggrin deficient skin, but only WY14643 significantly improved the skin barrier function.. Supplementation particularly with the PPARα agonist WY14643 improved the homeostasis and barrier function of filaggrin deficient skin models by normalization of the free fatty acid profile underlining the potential of PPAR agonists for the treatment of filaggrin-associated skin diseases.

Topics: Cells, Cultured; Docosahexaenoic Acids; Fatty Acids, Nonesterified; Fibroblasts; Filaggrin Proteins; Genotype; Humans; Intermediate Filament Proteins; Lipid Metabolism; Membrane Proteins; Permeability; Phenotype; PPAR alpha; PPAR gamma; Protein Precursors; Pyrimidines; RNA Interference; Signal Transduction; Skin; Skin Absorption; Testosterone; Thiazolidinediones; Time Factors; Transfection

Previous studies demonstrated that peroxisome-proliferator-activated receptor (PPAR)-alpha or PPAR-delta activation stimulates keratinocyte differentiation, is anti-inflammatory, and improves barrier homeostasis. Here we demonstrate that treatment of cultured human keratinocytes with ciglitazone, a PPAR-gamma activator, increases involucrin and transglutaminase 1 mRNA levels. Moreover, topical treatment of hairless mice with ciglitazone or troglitazone increases loricrin, involucrin, and filaggrin expression without altering epidermal morphology. These results indicate that PPAR-gamma activation stimulates keratinocyte differentiation. Additionally, PPAR-gamma activators accelerated barrier recovery following acute disruption by either tape stripping or acetone treatment, indicating an improvement in permeability barrier homeostasis. Treatment with PPAR-gamma activators also reduced the cutaneous inflammatory response that is induced by phorbol 12-myristate-13-acetate, a model of irritant contact dermatitis and oxazolone, a model of allergic contact dermatitis. To determine whether the effects of PPAR-gamma activators are mediated by PPAR-gamma, we next examined animals deficient in PPAR-gamma. Mice with a deficiency of PPAR-gamma specifically localized to the epidermis did not display any cutaneous abnormalites on inspection, but on light microscopy there was a modest increase in epidermal thickness associated with an increase in proliferating cell nuclear antigen (PCNA) staining. Key functions of the skin including permeability barrier homeostasis, stratum corneum surface pH, and water-holding capacity, and response to inflammatory stimuli were not altered in PPAR-gamma-deficient epidermis. Although PPAR-gamma activators stimulated loricrin and filaggrin expression in wild-type animals, however, in PPAR-gamma-deficient mice no effect was observed indicating that the stimulation of differentiation by PPAR-gamma activators is mediated by PPAR-gamma. In contrast, PPAR-gamma activators inhibited inflammation in both PPAR-gamma-deficient and wild-type mouse skin, indicating that the inhibition of cutaneous inflammation by these PPAR-gamma activators does not require PPAR-gamma in keratinocytes. These observations suggest that thiazolidindiones and perhaps other PPAR-gamma activators maybe useful in the treatment of cutaneous disorders.

Topics: Animals; Cell Differentiation; Dermatitis, Irritant; Epidermis; Female; Filaggrin Proteins; Homeostasis; Hypoglycemic Agents; Keratinocytes; Male; Mice; Mice, Hairless; Mice, Transgenic; Protein Precursors; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazolidinediones; Transcription Factors; Transglutaminases