Interleukin-13 overexpression by tax transactivation: a potential autocrine stimulus in human T-cell leukemia virus-infected lymphocytes.
The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein induces growth transformation and is critical for the pathogenesis of the HTLV-1-induced adult T-cell leukemia (ATL). It stimulates the cell cycle and transactivates cellular genes. Here we show that the expression of interleukin-13 (IL-13) is upregulated as a consequence of Tax in HTLV-1-transformed T cells and ATL-derived cultures. IL-13 exerts proliferative and antiapoptotic functions and is linked to leukemogenesis, since it stimulates Hodgkin lymphoma cells by an autocrine mechanism. Overexpression of IL-13 RNA and protein was confirmed in HTLV-1-positive and Tax-transformed cells. Induction of endogenous IL-13 levels in tax-transfected Jurkat cells and in conditional Tax-expressing transformed T lymphocytes suggested that Tax can replace signals required for IL-13 synthesis. For functional analysis, the IL-13 promoter and deletion variants were cloned into luciferase reporter plasmids. Experiments with transfected human T lymphocytes revealed a 16-fold stimulation of the IL-13 promoter by Tax. Experiments with Tax mutants indicated that none of the classical transactivation pathways (SRF, CREB, and NF-kappaB) is sufficient for the transactivation; at least two different Tax functions are required for full transactivation. The IL-13 promoter is stimulated via two elements; one is a NF-AT binding P element, and the other is a putative AP-1 site. The following observations suggest that IL-13 may stimulate HTLV-1-transformed cells by an autocrine mechanism: (i) the HTLV-1-transformed cells express the IL-13 receptor on their surface, and (ii) STAT6, a downstream effector of IL-13 signaling, is constitutively activated. Thus, in summary, Tax, by transactivating the promoter, induces IL-13 overexpression that possibly leads to an autocrine stimulation of HTLV-1-infected cells.
Wäldele
Katja
K
Institut für Klinische und Molekulare Virologie, Schlossgarten 4, D-91054 Erlangen, Germany.
Schneider
Grit
G
Ruckes
Tobias
T
Grassmann
Ralph
R
D019898:Autocrine Communication / Q000502:physiology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells / Q000821:virology; D015459:Leukemia-Lymphoma, Adult T-Cell; D018123:Receptors, Interleukin / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016356:Gene Products, tax; D018793:Interleukin-13; D018123:Receptors, Interleukin