calcipotriene and Dermatitis

Calcipotriol ameliorates psoriasis through inducing keratinocyte apoptosis and inhibiting nuclear factor kappa B (NF-κB) activation, while zinc finger protein A20 exhibits an anti-apoptotic effect on various types of cells.. To understand the potential role of A20 in calcipotriol function.. The A20 levels were evaluated in the psoriatic skins from both human patients and K14-vascular endothelial growth factor (VEGF) transgenic mice that received or did not receive topical calcipotriol treatment. The in vitro effect of calcipotriol on A20 expression and the downstream NF-κB pathway was studied using a model of human foreskin keratinocytes (HFKs) that were stimulated with psoriatic cytokines [M5, a cocktail of interleukin (IL)-1a, IL-17A, IL-22, Oncostatin M and tumour necrosis factor-α, each at 10 ng mL(-1) ].. A20 expression was enhanced in both psoriatic tissues and keratinocytes when compared with controls, but decreased on calcipotriol treatment. The transfection of A20 small interfering RNA (siRNA) improved cell differentiation, and inhibited psoriatic inflammation in a HFK model. Moreover, the nuclear expression of NF-κB p65 decreased on A20 downregulation in psoriatic tissues and keratinocytes. Interestingly, calcipotriol enhanced the binding of A20 to ring finger protein 114 (RNF114) and A20-binding inhibitor of NF-κB-1 (ABIN-1) in HFKs, two negative regulators of the NF-κB pathway.. Calcipotriol exhibits its antipsoriatic function through suppressing A20 expression and stabilizing negative regulators of the NF-κB pathway.

Topics: Administration, Cutaneous; Animals; Apoptosis; Calcitriol; Cell Differentiation; Cells, Cultured; Cytokines; Dermatitis; Dermatologic Agents; Down-Regulation; Female; Humans; Keratinocytes; Mice, Transgenic; NF-kappa B; Protein Binding; Psoriasis; RNA, Small Interfering; Signal Transduction; Skin; Transfection; Tumor Necrosis Factor alpha-Induced Protein 3

Chronic proliferative dermatitis (cpd) is a spontaneous mutation in C57BL/Ka mice (cpdm/cpdm). The dermatitis is characterized by redness, hairloss, scaling, pruritus and histologically by epithelial hyperproliferation, infiltration of eosinophils, macrophages and mast cells. Lesions similar to those in the skin occur in the esophagus and forestomach. In this paper, we describe the effect of drug treatments directed against epidermal hyperproliferation (calcipotriene and etretinate), against inflammation (corticosteroids and dapsone) and against pruritus (loratidine and capsaicin). The criteria used to objectively estimate the effect of the treatment were 1) macroscopic evaluation of the lesions (cpd score), 2) degree of epithelial hyperproliferation assessed by BrdU incorporation and epithelial thickness, and 3) microscopic evaluation of the inflammatory cells in the skin samples. Treatment of the cpdm/cpdm mice with calcipotriene (5 microg/day for 3 weeks) inhibited epidermal proliferation and the number of eosinophils. Systemic etretinate treatment (30 microg/g/day for 3 weeks) was not very effective. Topical corticosteroids (0.05 microg/day, for 3 weeks) exerted a therapeutic effect on the hyperproliferation and the number of eosinophils. Oral dapsone treatment (34 microg/g/day, for 5 weeks) reduced the BrdU incorporation in the skin and the epithelial thickness in the esophagus. The anti-histamine loratidine (orally, 1.7 microg/ g/day, for 4 weeks) reduced the severity of the lesions macroscopically, probably by suppressing the pruritus. Capsaicin (topically, 30 mM, for 5 weeks) also reduced the severity of the macroscopic observable lesions. Moreover, capsaicin reduced the dorsal and ventral epidermal thickness. The results from this and previous studies indicate that steroids (topically and systemically) and less strongly calcipotriene are the most effective treatments for the lesions observed in the cpdm/cpdm mice, since both hyperproliferation and the influx of eosinophils are reduced. Although the pathogenesis of the cpd lesions remains to be determined, our results indicate that the cpdm/cpdm mouse can be used to investigate new drugs for their possible application in chronic dermatitis.

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipruritics; Calcitriol; Capsaicin; Cell Division; Chronic Disease; Dapsone; Dermatitis; Etretinate; Keratolytic Agents; Loratadine; Mice; Mice, Inbred C57BL; Mutation

Topics: Administration, Cutaneous; Calcitriol; Child; Dermatitis; Dermatologic Agents; Female; Foot Dermatoses; Hamartoma; Humans; Infant; Leg Dermatoses; Male; Skin Diseases