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(American Journal of Pathology. 2005;166:843-855.)
© 2005 American Society for Investigative Pathology

A Cyclosporine-Sensitive Psoriasis-Like Disease Produced in Tie2 Transgenic Mice

Daniel Voskas*{dagger}, Nina Jones{dagger}, Paul Van Slyke*{dagger}, Celina Sturk*{dagger}, Wing Chang{ddagger}, Alex Haninec*{dagger}, Yael Olya Babichev{dagger}, Jennifer Tran{dagger}, Zubin Master*{dagger}, Stephen Chen*{dagger}, Nicole Ward§, Maribelle Cruz{dagger}, Jamie Jones{dagger}, Robert S. Kerbel*{dagger}, Serge Jothy{ddagger}, Lina Dagnino{ddagger}, Jack Arbiser||, Giannoula Klement** and Daniel J. Dumont*{dagger}{dagger}{dagger}

From the Department of Medical Biophysics,* University of Toronto, Toronto, Ontario, Canada; the Division of Molecular and Cellular Biology,{dagger} Sunnybrook and Women’s Research Institute, Toronto, Ontario, Canada; the Toronto-Sunnybrook Regional Cancer Centre,{dagger}{dagger} Toronto, Ontario, Canada; the Department of Anatomy,§ Case Western University, Cleveland, Ohio; the Department of Laboratory Medicine and Pathobiology,{ddagger} St. Michael’s Hospital, Toronto, Ontario, Canada; the Departments of Physiology/Pharmacology and Paediatrics, the University of Western Ontario, London, Ontario, Canada; the Child Health Research Institute and Lawson Health Research Institute,{ddagger} London, Ontario, Canada; the Department of Dermatology,|| Emory University School of Medicine, Atlanta, Georgia; and Department of Pediatric Oncology,** Dana-Farber Cancer Institute, Boston, Massachusetts

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.




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