Skin Suppression Research Articles

Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling.

P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumor suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and family members have been implicated in the direct regulation of VDR. This overview summarizes some of the implications of the cross-talk between vitamin D- and p53-signaling for carcinogenesis in the skin and other tissues.

Topical Application of Cream-emulsified CD86 siRNA Ameliorates Allergic Skin Disease by Targeting Cutaneous Dendritic Cells

Induction of the co-stimulatory molecule CD86 on dendritic cells (DCs) in the peripheral tissues is a critical event in triggering antigen-specific immune responses. In this study, we propose a new small interfering RNA (siRNA)-based therapy using cream-emulsified CD86 siRNA, targeting DCs for murine contact hypersensitivity (CH) and atopic dermatitis (AD)-like disease. Topical application of CD86 siRNA efficiently inhibited CH and markedly decreased the numbers of infiltrating CD86(+) or major histocompatibility complex (MHC) class II(+) cells in murine ear skin. The total number of cells, the percentage of hapten-carrying DCs, and their CD86 expression in the regional lymph nodes (RLNs) also significantly decreased. These results suggest that the silencing of CD86 in local DCs inhibits the recruitment and migration of DCs into the skin and RLNs, respectively, resulting in reduced antigen-specific local inflammation. The therapeutic efficacy of the CD86 siRNA was confirmed in AD-prone NC/Nga mice. Treatment produced marked amelioration in the clinical manifestations of AD and reduced the antigen-specific production of interleukin-4 (IL-4) and serum immunoglobulin E (IgE) and IgG1. Our results suggest that the targeting of cutaneous DCs by CD86 siRNA may be a promising strategy in the treatment of allergic skin disease.

Dermal Delivery of Topically Applied Oligonucleotides via Follicular Transport in Mouse Skin

Antisense oligodeoxynucleotides formulated in cream preparations are being examined in the clinic as topical therapy for psoriasis. To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topically applied phosphorothioate antisense oligonucleotide targeted to intercellular adhesion molecule-1 recently was shown to modulate cytokine-inducible target gene expression in engrafted human skin. In this study, we examined the route of entry into mouse skin of fluorochrome-tagged or naked second-generation 2'-O-methoxyethyl-modified oligonucleotides that react specifically with an antibody, using topical cream-based formulations. In hairless mouse skin, immunohistochemical analysis and fluorescence microscopy were unable to detect the presence of oligonucleotide in the epidermis or dermis following topical application although immunostaining was associated with the stratum corneum and fluorescein isothiocyanate-labeled oligonucleotide was observed in hair follicles. Kinetic analysis of oligonucleotide topically applied to hair-clipped BALB/c mouse skin showed early follicular localization, diffusion of oligonucleotide from the mid-follicle, and subsequent dermal accumulation. Saline formulation resulted in oligonucleotide remaining within the hair follicle. These results suggest that oligonucleotide penetration in skin involves a follicular route and further, that topical oligonucleotide therapy may be particularly well suited for altering physiology within the hair follicle and related structures.

Intercellular Adhesion Molecule-1 Suppression in Skin by Topical Delivery of Anti-Sense Oligonucleotides

We topically applied 20 nucleotide phosphorothioate intercellular adhesion molecule-1 anti-sense oligodeoxynucleotide in a cream formulation. It effectively inhibited tumor necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 in human skin transplanted on severe compromised immunodeficient mice. The effects were concentration dependent, sequence specific, and resulted from reduction of intercellular adhesion molecule-1 mRNA levels in the skin. Intravenous administration of the drug did not show pharmacologic effects, probably due to insufficient drug concentrations in skin. Topical delivery, however, produced a rapid and a significantly higher accumulation of oligodeoxynucleotide in the epidermis and dermis. The results strongly suggest that topically applied anti-sense oligonucleotides can be delivered to target sites in the skin and may be of considerable value in the treatment of psoriasis and other inflammatory skin disorders.