Identification of TSLP-dependent mediators in a calcipotriol (Dovonex®) driven mouse model of skin inflammation (140.16)

Abstract

Abstract The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is sufficient to induce asthma or atopic dermatitis (AD)-like phenotypes when selectively overexpressed in transgenic mice. Although T and B cells have been reported to be dispensable for the TSLP-induced inflammation in these models, little is known about the downstream pathways or mediators involved in the inflammatory response driven by TSLP. Topical treatment with vitamin D3 (1α,25-(OH)2D3) or MC903, the low-calcemic analog of vitamin D3, has been shown to induce TSLP expression in epidermal keratinocytes. This induction resulted in an AD-like phenotype similar to that seen in TSLP transgenic mice. 0.005% calcipotriol (Dovonex®) is a synthetic, low-calcemic vitamin D3 analog which is FDA-approved for the treatment of psoriasis. Following topical application of Dovonex® onto mouse ears, TSLP mRNA expression increased over time. Concomitant increases in CCL17/TARC, CCL22/MDC, and IL-6 mRNA were also observed. These increases were dependent on TSLP as an antibody that blocked TSLP signaling abrogated the response. Similarly, a variety of TSLP-dependent protein analytes were increased in the skin following application of Dovonex®. Together these data identify TSLP-dependent mediators that may play a role in the development of skin inflammatory diseases such as atopic dermatitis.