TPA induction leads to a Th17-like response in transgenic K14/VEGF mice: a novel in vivo screening model of psoriasis.
Psoriasis is a common chronic inflammatory skin disease, characterized by epidermal hyperplasia, immune cell infiltration, increased dermal angiogenesis and local up-regulation of a variety of inflammatory mediators. Psoriasis is thought to be driven primarily by CD4(+) T cells with a T(h)1 and/or T(h)17 phenotype. Transgenic keratin 14 (K14)/vascular endothelial growth factor (VEGF) mice have previously been reported to develop a psoriasis-like phenotype. The aim of this study was to further characterize the model for validation as an in vivo screening model of psoriasis. Inflammation was induced in the ear skin with five topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA) and a significantly increased inflammation was found in TPA-induced K14/VEGF transgenic animals compared with wild-type mice. The amount of VEGF in the ear tissue was significantly elevated resulting in increased dermal angiogenesis. Furthermore, intense epidermal hyperplasia, CD3(+) infiltration and significantly increased amounts of (TNF) tumor necrosis factor alpha, IL-1 beta, IL-6, IL-12/23p40, IL-12p70, IL-22 and IL-17 were detected in the inflamed ear skin. This cytokine profile strongly suggests a T(h)17-mediated inflammation. All findings were a result of induced over-expression of VEGF. Topical treatment with betamethasone-17-valerate (BMS) significantly reduced ear skin inflammation and epidermal hyperplasia and also decreased the CD3(+) infiltration. In conclusion, the TPA-induced phenotype in K14/VEGF animals displayed several features of psoriasis, including a T(h)17 cytokine profile and a chronic-like progression, and can be used as an in vivo screening model of psoriasis.
Hvid
Henning
H
Section of Dermatology, Department of Pharmacology, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
Teige
Ingrid
I
Kvist
Peter Helding
PH
Svensson
Lars
L
Kemp
Kåre
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001624:Betamethasone Valerate / Q000008:administration & dosage; D004195:Disease Models, Animal; D017573:Focal Epithelial Hyperplasia / Q000097:blood / Q000139:chemically induced / Q000209:etiology; D020381:Interleukin-17 / Q000378:metabolism; D053547:Keratin-14 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D010031:Otitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D010703:Phorbol Esters / Q000494:pharmacology; D011565:Psoriasis / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D012867:Skin / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D020381:Interleukin-17; D053547:Keratin-14; D010703:Phorbol Esters; D042461:Vascular Endothelial Growth Factor A; D001624:Betamethasone Valerate