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. 2015 Mar;3(1):32-43.
doi: 10.1002/iid3.48. Epub 2015 Feb 16.

TSLP is differentially regulated by vitamin D3 and cytokines in human skin

Janneke Landheer  1 , Barbara Giovannone  1 , Svetlana Sadekova  2 , Sandra Tjabringa  1 , Claudia Hofstra  3 , Koen Dechering  3 , Carla Bruijnzeel-Koomen  1 , Charlie Chang  4 , Yu Ying  2 , Rene de Waal Malefyt  5 , DirkJan Hijnen  1 , Edward Knol  6
Affiliations

TSLP is differentially regulated by vitamin D3 and cytokines in human skin

Janneke Landheer et al. Immun Inflamm Dis. 2015 Mar.

Abstract

Thymic stromal lymphopoietin (TSLP) plays an important role in allergic diseases and is highly expressed in keratinocytes in human lesional atopic dermatitis (AD) skin. In nonlesional AD skin TSLP expression can be induced by applying house dust mite allergen onto the skin in the atopy patch test. Several studies have demonstrated that the induction of TSLP expression in mouse skin does not only lead to AD-like inflammation of the skin, but also predisposes to severe inflammation of the airways. In mice, TSLP expression can be induced by application of the 1,25-dihydroxyvitamin D3 (VD3) analogue calcipotriol and results in the development of eczema-like lesions. The objective is to investigate the effect of VD3 (calcitriol) or calcipotriol on TSLP expression in normal human skin and skin from AD patients. Using multiple ex vivo experimental setups, the effects of calci(po)triol on TSLP expression by normal human skin, and skin from AD patients were investigated and compared to effects of calcipotriol on mouse and non-human primates (NHP) skin. No induction of TSLP expression (mRNA or protein) was observed in human keratinocytes, normal human skin, nonlesional AD skin, or NHP skin samples after stimulation with calcipotriol or topical application of calcitriol. The biological activity of calci(po)triol in human skin samples was demonstrated by the increased expression of the VD3-responsive Cyp24a1 gene. TSLP expression was induced by cytokines (IL-4, IL-13, and TNF-α) in skin samples from all three species. In contrast to the findings in human and NHP, a consistent increase in TSLP expression was confirmed in mouse skin biopsies after stimulation with calcipotriol. VD3 failed to induce expression of TSLP in human or monkey skin in contrast to mouse, implicating careful extrapolation of this often-used mouse model to AD patients.

Keywords: Allergy; TSLP; VDRE; atopic dermatitis; vitamin D3.

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Figures

Figure 1
Figure 1
Effect of calcipotriol on differentiated primary human keratinocytes. Differentiated keratinocytes were stimulated with calcipotriol alone, a mix of cytokines (IL-13,IL-4, TNF-α) (Cyts) and a combination of the two treatments for 8 or 24 h. (a) TSLP mRNA expression (n = 4); (b) TSLP protein expression (n = 3); (c) Cyp24 mRNA expression (n = 4). The control for cytokines stimulated cells is medium, in the other conditions the control is DMSO. Data are shown as mean +/− SEM.
Figure 2
Figure 2
Effects of calcipotriol on TSLP expression in normal human skin biopsies at 24 and 48 h of treatment. (a) TSLP mRNA expression; (b) TSLP protein expression; (c) Cyp24 gene expression. Data are representative of three independent skin donors and are shown as mean ± SEM.; *P < 0.05.
Figure 3
Figure 3
Effects of topical application of calcitriol on TSLP expression in normal human skin samples. Biopsies were cultured in an air-liquid interphase manner for 24, 48, and 72 h post topical application of calcitriol and petrolatum control (30 min). Cytokines mixture was added to the culture medium of untreated skin biopsies as positive control for TSLP stimulation. (a) TSLP mRNA expression; (b) TSLP protein expression; (c) Cyp24 expression. Data are representative of three independent skin donors and are shown as mean ± SEM.; *P <  0.05.
Figure 4
Figure 4
Effects of calcipotriol on nonlesional AD skin biopsies (n = 6) stimulated for 48 h. (a) TSLP mRNA expression; (b) TSLP protein expression; (c) Cyp24 mRNA expression. Data are shown as mean ± SEM.; *P < 0.05.
Figure 5
Figure 5
Calcipotriol induces TSLP protein expression in mouse skin biopsies (n = 4) after 24 h stimulation. Each dot represents TSLP levels in a culture of six biopsies per mouse.
Figure 6
Figure 6
Effects of the VD3 analogue calcipotriol on Cynomolgus monkey skin biopsies. (a) TSLP protein expression (n = 4) and (b) Cyp24 mRNA expression (n = 3), after 48 h stimulation. Data are shown as mean ± SEM; *P < 0.05.
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