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Journal of Virology, June 2004, p. 6081-6090, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6081-6090.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Interleukin-13 Overexpression by Tax Transactivation: a Potential Autocrine Stimulus in Human T-Cell Leukemia Virus-Infected Lymphocytes

Katja Wäldele, Grit Schneider, Tobias Ruckes,{dagger} and Ralph Grassmann*

Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany

Received 5 November 2003/ Accepted 9 February 2004

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-{kappa}B) 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.

* Corresponding author. Mailing address: Institut für Klinische und Molekulare Virologie, Schlossgarten 4, D-91054 Erlangen, Germany. Phone: 49-9131-8526784. Fax: 49-9131-8526493. E-mail: Ralph.Grassmann{at}viro.med.uni-erlangen.de.

{dagger} Present address: Artus GmbH, 22767 Hamburg, Germany.

Journal of Virology, June 2004, p. 6081-6090, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6081-6090.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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