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: Daniel Voskas, Nina Jones, Paul Van Slyke, Celina Sturk, Wing Chang, Alex Haninec, Yael Olya Babichev, Jennifer Tran, Zubin Master, Stephen Chen, Nicole Ward, Maribelle Cruz, Jamie Jones, Robert S Kerbel, Serge Jothy, Lina Dagnino, Jack Arbiser, Giannoula Klement, Daniel J Dumont
• Journal: The American journal of pathology (Am J Pathol) Vol. 166 Issue 3 Pg. 843-55 (Mar 2005) ISSN: 0002-9440 [Print] United States
• PMID: 15743796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiopoietins
• Immunosuppressive Agents
• Lectins
• Vascular Endothelial Growth Factor A
• Cyclosporine
• Receptor, TIE-2
• Tetracycline
• Doxycycline

Topics

• Angiopoietins (metabolism)
• Animals
• Blotting, Western
• Cell Line
• Cyclosporine (pharmacology)
• Doxycycline (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Epidermis (metabolism)
• Gene Expression Regulation
• Genotype
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Immunosuppressive Agents (pharmacology)
• Inflammation
• Keratinocytes (cytology)
• Lac Operon
• Lectins (metabolism)
• Mice
• Mice, Transgenic
• Models, Genetic
• Phenotype
• Psoriasis (drug therapy)
• Receptor, TIE-2 (genetics)
• Signal Transduction
• Skin (metabolism, pathology)
• Tetracycline (pharmacology)
• Time Factors
• Transgenes
• Vascular Endothelial Growth Factor A (metabolism)