Human T-cell lymphotropic virus type I (HTLV-I) activates IL-15Ralpha expression via NF-kappaB and interferon regulatory elements.

摘要

Human T-cell Lymphotropic Virus Type-I (HTLV-I) is the causative agent of both Adult T Cell Leukemia (ATL) and HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Interleukin-15 is a proliferative cytokine that is elevated in diseases caused by HTLV-I. In this dissertation, we demonstrated that interleukin 15 receptor alpha (IL-15Rα), the IL-15 specific binding receptor, mRNA levels were also elevated in HTLV-I infected cells. We also showed that IL-15Rα protein levels were elevated in HTLV-I infected cells using a newly developed polyclonal antibody directed against the receptor. We showed that transient HTLV-I Tax expression lead to increased IL-15Rα mRNA levels. In addition, by using a reporter construct that hears the human IL-15Rα promoter, we demonstrated that Tax expression increased activated IL-15Rα promoter activity. Using promoter deletion constructs and gel shift analysis, we defined a functional NF-κB binding motif in the human IL-15Rα promoter, suggesting that Tax activation of IL-15Rα is due, in part, to the induction of NF-κB. In addition, we demonstrated that an Interferon Regulatory Element (IRF-E) within the IL-15Rα promoter was also crucial for Tax-induced activation. This activation was mediated by IFR-4, an interferon regulatory factor elevated in ATL and HTLV-I infected cells These data indicate that IL-15Rα is transcriptionally regulated by the HTLV-I Tax protein through the action of NF-κB and IRF-4. These findings suggest a role for IL-15Rα in aberrant T cell proliferation observed in HTLV-I associated diseases.