A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice.
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.
Voskas
Daniel
D
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Jones
Nina
N
Van Slyke
Paul
P
Sturk
Celina
C
Chang
Wing
W
Haninec
Alex
A
Babichev
Yael Olya
YO
Tran
Jennifer
J
Master
Zubin
Z
Chen
Stephen
S
Ward
Nicole
N
Cruz
Maribelle
M
Jones
Jamie
J
Kerbel
Robert S
RS
Jothy
Serge
S
Dagnino
Lina
L
Arbiser
Jack
J
Klement
Giannoula
G
Dumont
Daniel J
DJ
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
D042682:Angiopoietins; D007166:Immunosuppressive Agents; D037102:Lectins; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine; D042787:Receptor, TIE-2; D013752:Tetracycline; D004318:Doxycycline
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1904-9
10051567
Immunity. 1998 Nov;9(5):677-86
9846489
Development. 1999 May;126(10):2093-102
10207135
Transgenic Res. 1998 Nov;7(6):421-7
10341450
Hum Mol Genet. 1999 Jul;8(7):1279-89
10369874
Invest Ophthalmol Vis Sci. 1999 Aug;40(9):1912-20
10440243
Arch Dermatol. 1999 Sep;135(9):1104-10
10490116
Development. 1999 Oct;126(20):4569-80
10498691
Blood. 2005 Feb 15;105(4):1523-30
15498854
Br J Dermatol. 1999 Dec;141(6):1054-60
10606852
Science. 1999 Dec 24;286(5449):2511-4
10617467
Circ Res. 2000 Jan 7-21;86(1):24-9
10625301
Lab Invest. 2000 Jan;80(1):99-115
10653008
Circ Res. 2000 May 12;86(9):952-9
10807867
Nat Cell Biol. 2000 Oct;2(10):737-44
11025665
J Invest Dermatol. 2000 Nov;115(5):771-7
11069613
J Investig Dermatol Symp Proc. 2000 Dec;5(1):3-9
11147672
Cardiovasc Res. 2001 Feb 16;49(3):659-70
11166279
Circ Res. 2001 Feb 2;88(2):167-74
11157668
J Exp Med. 2001 Mar 5;193(5):607-20
11238591
Trends Cell Biol. 2001 Apr;11(4):143-6
11306276
Cancer Res. 2001 Apr 15;61(8):3450-7
11309307
J Exp Med. 2001 May 7;193(9):1005-14
11342585
J Invest Dermatol. 2001 May;116(5):713-20
11348459
EMBO Rep. 2001 May;2(5):438-45
11375937
Exp Dermatol. 2001 Jun;10(3):175-83
11380613
J Biol Chem. 2001 Jun 29;276(26):23531-8
11319226
Genes Dev. 2001 Oct 1;15(19):2520-32
11581158
Cancer Res. 2002 Jan 15;62(2):580-8
11809713
Br J Cancer. 2002 Feb 12;86(4):645-51
11870550
FASEB J. 2002 Apr;16(6):555-64
11919158
Semin Cell Dev Biol. 2002 Feb;13(1):19-27
11969368
Arthritis Res. 2002;4(3):201-8
12010571
J Biol Chem. 2003 Jan 17;278(3):1721-7
12427764
Mol Cell Biol. 2003 Apr;23(8):2658-68
12665569
Blood. 2003 Jul 1;102(1):161-8
12649136
J Cell Sci. 2003 Sep 1;116(Pt 17):3635-43
12876214
Mol Hum Reprod. 2003 Nov;9(11):663-9
14561809
J Cell Sci. 2004 Mar 1;117(Pt 7):1055-63
14970256
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13291-5
15331785
Am J Pathol. 1988 Apr;131(1):12-8
2451427
Genes Dev. 1994 Aug 15;8(16):1897-909
7958865
Am J Pathol. 1995 Mar;146(3):580-8
7887440
Nature. 1995 Jul 6;376(6535):70-4
7596437
Cell. 1996 Dec 27;87(7):1171-80
8980224
Cell. 1996 Dec 27;87(7):1181-90
8980225
Nat Med. 1997 Feb;3(2):183-8
9018237
Annu Rev Immunol. 1997;15:707-47
9143705
Blood. 1997 Jun 15;89(12):4317-26
9192754
Science. 1997 Jul 4;277(5322):55-60
9204896
Pathobiology. 1997;65(5):271-86
9459497
J Invest Dermatol. 1998 Jul;111(1):1-6
9665379
Circ Res. 1998 Aug 10;83(3):233-40
9710115
Oncogene. 1998 Sep 3;17(9):1097-108
9764820
Science. 1998 Oct 16;282(5388):468-71
9774272
J Invest Dermatol. 1999 Apr;112(4):405-10
10201521