Combined Maxacalcitol/Betamethasone Butyrate Propionate Ointment Possesses Long-Term Sustained Effects of Inducing Regulatory T Cells and Downregulating the Th17 Response, Even After Discontinuation of Its Application in Imiquimod-Induced Psoriasiform Dermatitis.

Abstract

We often experience sustained improvement, even after discontinuation of treatment in psoriasis lesions treated with topical vitamin D(VD) or the combination of topical corticosteroids and VD. However, the underlying mechanisms of these sustained effects remain unclear. We explored mechanisms for the sustained effects of maxacalcitol (MCT) and combined MCT/betamethasone butyrate propionate (BBP) ointments using a murine psoriasiform dermatitis model induced by imiquimod (IMQ). IMQ was applied once daily to the shaved backs of mice for 6 days to induce psoriasiform dermatitis. MCT, BBP, combined MCT/BBP ointment, or their vehicles were treated for 3 days prior to IMQ application. IMQ was reapplied after 1, 2, or 3 weeks from the first IMQ application to investigate the sustained effects of their ointments. In the first application of IMQ, the administration of MCT, BBP, or MCT/BBP ointment improved clinical and pathological manifestations and reduced Th17-related cytokines. Treatment with MCT or MCT/BBP showed an increase in IL-10 mRNA expression and a higher count of Foxp3cells within the skin, but not in those with BBP. The induction of IL-10 by MCT and MCT/BBP persisted until reapplication of IMQ 2 weeks later, although their effects diminished 3 weeks later. The reduction in Th17-related cytokines was maintained up to 3 weeks later in MCT/BBP, whereas it was not observed 2 weeks later in MCT. In conclusion, MCT and MCT/BBP showed long-term effects by induction of regulatory T cells and IL-10. Additionally, MCT/BBP downregulated Th17-related cytokines, which could contribute to the sustained improvement after discontinuation observed in clinical practice.