Enhanced tumorigenesis in HTLV-1 tax-transgenic mice deficient in interferon-gamma.
The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon-gamma (IFN-gamma) in HTLV-1-infected CD4(+) cells and Tax-transgenic tumors. We examined the role of IFN-gamma in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-gamma. IFN-gamma(-/-) Tax(+)-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor-beta (IL-2Rbeta) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN-gamma(-/-) Tax(+) transgenic mice. IFN-gamma(-/-) tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-gamma(+/-) or IFN-gamma(+/+) Tax(+) mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax(+)IFN-gamma(-/-) mice compared with Tax(+)IFN-gamma(+/+) littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN-gamma results in down-regulation of tumor necrosis factor-alpha (TNF-alpha) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN-gamma contributes to host resistance against HTLV-induced tumors through an angiostatic effect.
Department of Internal Medicine, Washington University School of Medicine, 660 S Euclid Ave, Box 8069, St Louis, MO 63110, USA.
Shibani
S
Mitra-Kaushik
John
J
Harding
Jay
J
Hess
Robert
R
Schreiber
Lee
L
Ratner
D017668:Age of Onset; D000818:Animals; D045744:Cell Line, Tumor; D006800:Deltaretrovirus Infections / Q000276:immunology*; D005434:Flow Cytometry; D016356:Gene Products, tax / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism
D016356:Gene Products, tax; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma