Topical Vitamin D3 and Low-Calcemic Analogs Induce Thymic Stromal Lymphopoietin in Mouse Keratinocytes and Trigger an Atopic Dermatitis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 31; pp. 11736 - 11741
• Main Authors: Li, Mei, Hener, Pierre, Zhang, Zhikun, Kato, Shigeaki, Metzger, Daniel, Chambon, Pierre
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01-08-2006; National Acad Sciences
• Subjects: Administration, Topical; Animals; Biochemistry, Molecular Biology; Biological Sciences; Calcitriol; Calcitriol - administration & dosage; Calcitriol - adverse effects; Calcitriol - analogs & derivatives; Calcitriol - immunology; Calcium; Calcium - metabolism; Cells, Cultured; Cholecalciferols; Cytokines; Cytokines - genetics; Cytokines - immunology; Dermatitis; Dermatitis, Atopic; Dermatitis, Atopic - chemically induced; Dermatitis, Atopic - immunology; Dermatologic Agents; Dermatologic Agents - administration & dosage; Dermatologic Agents - adverse effects; Dermatologic Agents - immunology; Dimerization; Ethanol; Female; Genotype & phenotype; Humans; Inflammation; Keratinocytes; Keratinocytes - cytology; Keratinocytes - immunology; Life Sciences; Lymphocyte receptors; Mast cells; Mice; Mice, Knockout; Mice, Transgenic; Molecular biology; Receptors; Receptors, Calcitriol; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Receptors, Retinoic Acid; Receptors, Retinoic Acid - agonists; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor gamma; Retinoid X Receptor alpha; Retinoid X Receptor alpha - agonists; Retinoid X Receptor alpha - genetics; Retinoid X Receptor alpha - metabolism; Retinoid X Receptor beta; Retinoid X Receptor beta - agonists; Retinoid X Receptor beta - genetics; Retinoid X Receptor beta - metabolism; Retinoids; Retinoids - immunology; Skin; Skin - cytology; Skin - drug effects; Skin - pathology; T lymphocytes; Thymic Stromal Lymphopoietin; Vitamin D; Vitamins; Vitamins - administration & dosage; Vitamins - adverse effects; Vitamins - chemistry; Vitamins - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604575103

We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyteselective ablation of retinoid X receptors (RXRs) -α and -β in the mouse ($RXR\alpha\beta^{ep-/-} mice$), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [lα,25(OH)₂D₃; calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in $RXR\alpha\beta^{ep-/-}$ mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RARγ-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with lα,25-(OH)₂D₃. Our data demonstrate that RXR/ vitamin D receptor and RXR/retinoic acid receptor-γ heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.