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Abstract Endogenous retinoids like all- trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists.

Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties. Introduction The nuclear hormone receptors retinoic acid receptors (RAR) α, β, and γ and retinoid X receptors (RXR) α, β, and γ are ligand-dependent transcription factors that can be activated by retinoids.

RAR-RXR heterodimers regulate the expression of multiple genes in skin and various other tissues, while their transcriptional activity is dependent on the RAR-activating ligand –. The most abundant RAR and RXR subtypes in skin are RXRα and RARγ, followed by lower quantities of RARα. Since retinoid receptors exhibit tissue and cell type-specific distribution patterns, functional specificity of each subtype is suggested –. Moreover, RAR and RXR subtypes differ in ligand specificity and/or affinity, –, therefore, it can be assumed that their contribution to gene expression patterns in skin differs, depending on quantitative receptor distribution, on the nature and level of co-regulators, as well as on available retinoid receptor-selective agonists and antagonists. RAR-RXR-mediated signaling pathways induced by retinoids are essentially involved in immune-modulatory events –, and skin physiology through their role in the regulation of several aspects of skin cell proliferation, differentiation, apoptosis, and epidermal barrier function,. Retinoid metabolism and concentrations in skin are tightly regulated ensuring sufficient levels of the endogenous pan-RAR activator all- trans retinoic acid (ATRA),,.

However, alterations in retinoid metabolism, signaling and concentrations have been observed in various dermatoses, such as psoriasis, ichthyosis, and recently in a study by our group in atopic dermatitis. Altered retinoid-mediated signaling in skin of these patients may also be a result of activation or antagonism of specific retinoid receptor subtypes under disease conditions. In order to dissect retinoid-mediated signaling in skin, mice were treated topically for two weeks with selective RAR and RXR agonists or antagonists. Our aim was to determine the effect of RAR subtype-selective and RXR activation or antagonism on the expression of genes involved in retinoid metabolism and signaling, as well as epidermal barrier homeostasis and skin-based immune regulation. The outcome of the present study will help to identify pathways and genes that are selectively regulated by RARα, RARγ, or RXR in the skin of mice. This might allow for conclusions regarding the involvement of subtype-specific retinoid receptor-mediated signaling in various skin diseases and may suggest alternative therapeutic strategies. Sims 3 caches sunset valley objectcache download.

Retinoid Receptor-specific Agonists and Antagonists ATRA was a gift from BASF (Ludwigshafen, D) and the synthetic RXR activator LG268 was kindly provided by Ligand Pharmaceuticals (San Diego, CA). Synthetic agonists selective for RARα (BMS753) and RARγ (BMS189961) were prepared in our laboratories as described in the original patents, with the yields indicated as supporting information ( and ). The RARα-specific antagonist (BMS614) was made following the patented procedure developed at BMS, as detailed in the supporting information section (). The RARγ-selective antagonist (UVI2041) was prepared by the condensation of the ester 15 derived from chalcone 14 with hydroxylamine, followed by hydrolysis as described in supplements (). Danda pindagalu kannada serial title song full. The RAR pan-antagonist/inverse agonist (BMS493) and the RXR pan-antagonist (UVI3003) were synthesized according to reported procedures,. The purity of the synthesized compounds was determined to be greater than 95% by HPLC after crystallization. We have confirmed that these retinoids are stable when stored as solids or in solution at −78°C, and during the time frame of biological experiments.