title: Calcipotriol and betamethasone dipropionate exert additive inhibitory effects on the cytokine expression of inflammatory dendritic cell-Th17 cell axis in psoriasis.
abstract: BACKGROUND
  Psoriasis vulgaris is characterised by epidermal hyper-proliferation and infiltration of immune cells including dendritic cells (DCs) and T cells. The inflammation is driven by a complex interplay between immune and skin cells involving interleukin (IL)-17A, IL-23 and TNF-α as key drivers. The calcipotriol/betamethasone dipropionate two-compound fixed combination product is widely used for topical treatment of psoriasis. However, the mechanism behind its high efficacy has not been elucidated in detail.
  
  
  OBJECTIVE
  Here, we investigated and compared the immune modulatory effects of betamethasone, calcipotriol and the combination in ex vivo cultures of psoriatic skin and in vitro cultures of primary human cells that recapitulate key cellular activities of psoriatic inflammation.
  
  
  METHODS
  The immune modulatory effect of the treatments on psoriatic skin and on in vitro differentiated Th1/Th17 cells, Tc1/Tc17 cells, monocyte-derived inflammatory dendritic cells and primary keratinocytes was assessed by a panel of inflammatory and phenotypic related transcription factors and cytokines. The expression was evaluated by both gene and protein analysis.
  
  
  RESULTS
  Compared to vehicle control or mono-treatments, the effect of calcipotriol/betamethasone combination was significantly better in inhibiting the secretion of IL-17A and TNF-α in psoriatic skin. Additionally, the two components showed additive inhibitory effects on secretion of IL-23 and TNF-α by DCs, of IL-17A and TNF-α by both CD4(+) and CD8(+) T cells and reduced inflammatory responses in Th17-stimulated keratinocytes. Furthermore, calcipotriol was found to enhance IL-10 secretion in psoriatic skin and in human T cells, to induce secretion of type 2 cytokines by T cells and, lastly, to significantly modulate the differentiation of DCs and T cells.
  
  
  CONCLUSIONS
  In summary, we demonstrate a unique and supplementary immune modulatory effect of calcipotriol/betamethasone combination on TNF-α and IL-23/Th17 immune axis, supporting the superior clinical efficacy of the combination product compared to the respective mono-treatments in psoriasis patients.
authors.affiliation: Department of Skin Inflammation Pharmacology, LEO Pharma A/S, Industriparken 55, Ballerup, Denmark. Electronic address: paola.lovato@leo-pharma.com.
authors.forename: Paola
authors.initials: P
authors.lastname: Lovato
authors.affiliation: Department of Skin Inflammation Pharmacology, LEO Pharma A/S, Industriparken 55, Ballerup, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Norsgaard
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tokura
authors.affiliation: Department of Clinical Pharmacology, LEO Pharma A/S, Industriparken 55, Ballerup, Denmark.
authors.forename: Mads A
authors.initials: MA
authors.lastname: Røpke
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D001623:Betamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D000305:Adrenal Cortex Hormones; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C055085:calcipotriene; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone; D002117:Calcitriol
keywords: Calcipotriol; Cell differentiation and activation; Immunomodulation; Inflammation; Psoriasis