title: A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice.
abstract: Psoriasis is a common, persistent skin disorder characterized by recurrent erythematous lesions thought to arise as a result of inflammatory cell infiltration and activation of keratinocyte proliferation. Unscheduled angiogenic growth has also been proposed to mediate the pathogenesis of psoriasis although the cellular and molecular basis for this response remains unclear. Recently, a role for the angiopoietin signaling system in psoriasis has been suggested by studies that demonstrate an up-regulation of the tyrosine kinase receptor Tie2 (also known as Tek) as well as angiopoietin-1 and angiopoietin-2 in human psoriatic lesions. To examine temporal expression of Tie2, we have developed a binary transgenic approach whereby expression of Tie2 can be conditionally regulated by the presence of tetracycline analogs in double-transgenic mice. A psoriasis-like phenotype developed in double-transgenic animals within 5 days of birth and persisted throughout adulthood. The skin of affected mice exhibited many cardinal features of human psoriasis including epidermal hyperplasia, inflammatory cell accumulation, and altered dermal angiogenesis. These skin abnormalities resolved completely with tetracycline-mediated suppression of transgene expression, thereby illustrating a complete dependence on Tie2 signaling for disease maintenance and progression. Furthermore, the skin lesions in double-transgenic mice markedly improved after administration of the immunosuppressive anti-psoriatic agent cyclosporine, thus demonstrating the clinical significance of this new model.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Voskas
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.forename: Paul
authors.initials: P
authors.lastname: Van Slyke
authors.forename: Celina
authors.initials: C
authors.lastname: Sturk
authors.forename: Wing
authors.initials: W
authors.lastname: Chang
authors.forename: Alex
authors.initials: A
authors.lastname: Haninec
authors.forename: Yael Olya
authors.initials: YO
authors.lastname: Babichev
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tran
authors.forename: Zubin
authors.initials: Z
authors.lastname: Master
authors.forename: Stephen
authors.initials: S
authors.lastname: Chen
authors.forename: Nicole
authors.initials: N
authors.lastname: Ward
authors.forename: Maribelle
authors.initials: M
authors.lastname: Cruz
authors.forename: Jamie
authors.initials: J
authors.lastname: Jones
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Serge
authors.initials: S
authors.lastname: Jothy
authors.forename: Lina
authors.initials: L
authors.lastname: Dagnino
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.forename: Giannoula
authors.initials: G
authors.lastname: Klement
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
mesh_terms: D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology; D007763:Lac Operon; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D010641:Phenotype; D011565:Psoriasis / Q000188:drug therapy*; D042787:Receptor, TIE-2 / Q000235:genetics*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042682:Angiopoietins; D007166:Immunosuppressive Agents; D037102:Lectins; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine; D042787:Receptor, TIE-2; D013752:Tetracycline; D004318:Doxycycline
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