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Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site
J M Mariner1, V Lantz, T A Waldmann
1Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. marinerj@mail.nih.gov
Abstract:
IL-15 mRNA levels are increased in diseases caused by human T cell lymphotropic virus type I (HTLV-I). In this study, we demonstrated that IL-15Ralpha, the IL-15-specific binding receptor, mRNA and protein levels were also elevated in HTLV-I-infected cells. We showed that transient HTLV-I Tax expression lead to increased IL-15Ralpha mRNA levels. In addition, by using a reporter construct that bears the human IL-15Ralpha promoter, we demonstrated that Tax expression increased promoter activity by at least 4-fold. Furthermore, using promoter deletion constructs and gel shift analysis, we defined a functional NF-kappaB-binding motif in the human IL-15Ralpha promoter, suggesting that Tax activation of IL-15Ralpha is due, in part, to the induction of NF-kappaB. These data indicate that IL-15Ralpha is transcriptionally regulated by the HTLV-I Tax protein through the action of NF-kappaB. These findings suggest a role for IL-15Ralpha in aberrant T cell proliferation observed in HTLV-I-associated diseases.
Insights
Human T cell lymphotropic virus type I (HTLV-I) infection elevates Interleukin-15 receptor alpha (IL-15Ralpha). The HTLV-I Tax protein upregulates IL-15Ralpha via NF-kappaB, suggesting a role in disease.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Interleukin-15 (IL-15) mRNA levels are elevated in diseases associated with human T cell lymphotropic virus type I (HTLV-I).
- IL-15Ralpha is the specific binding receptor for IL-15.
Purpose of the Study:
- To investigate the role of IL-15Ralpha in HTLV-I infection.
- To elucidate the mechanism by which HTLV-I Tax protein influences IL-15Ralpha expression.
Main Methods:
- Quantification of IL-15Ralpha mRNA and protein levels in HTLV-I-infected cells.
- Analysis of IL-15Ralpha promoter activity using reporter constructs.
- Investigation of the role of NF-kappaB in Tax-mediated IL-15Ralpha regulation through promoter deletion and gel shift assays.
Main Results:
- IL-15Ralpha mRNA and protein levels were significantly increased in HTLV-I-infected cells.
- Transient expression of HTLV-I Tax protein led to elevated IL-15Ralpha mRNA levels.
- Tax expression increased IL-15Ralpha promoter activity by over 4-fold, mediated by NF-kappaB binding to a specific motif.
Conclusions:
- IL-15Ralpha is transcriptionally regulated by the HTLV-I Tax protein.
- The Tax protein activates IL-15Ralpha expression, in part, through the induction of NF-kappaB.
- Upregulation of IL-15Ralpha may contribute to aberrant T cell proliferation in HTLV-I-associated diseases.