IFN Regulatory Factor 4 Participates in the Human T Cell Lymphotropic Virus Type I-Mediated Activation of the IL-15 Receptor α Promoter

Abstract

IL-15Rα mRNA and protein levels are increased in human T cell lymphotropic virus type-I (HTLV-I)-associated adult T cell leukemia. Previously, we demonstrated that IL-15Rα expression was activated by HTLV-I Tax, in part, through the action of NF-κB. However, there appeared to be additional motifs within the IL-15Rα promoter that were responsive to HTLV-I Tax. In this study, we demonstrated that IL-15Rα mRNA expression was activated in human monocytes by IFN treatment, suggesting a role for IFN regulatory factors (IRFs) in IL-15Rα transcription. In addition, an IRF element within the Tax-responsive element of the IL-15Rα promoter was necessary for maximal Tax-induced activation of this promoter. Furthermore, we demonstrated that IRF-4, a transcription factor known to be elevated in HTLV-I-infected cells, activated the IL-15Rα promoter. Inhibition of IRF-4 action lead to reduced Tax-induced activation of the IL-15Rα promoter, while inhibition of both IRF-4 and NF-κB severely inhibited the Tax-induced activation of this promoter. These findings suggest a role for both NF-κB and IRF-4 in the transcriptional regulation of IL-15Rα by HTLV-I Tax. It is possible that the HTLV-I Tax-mediated induction of IL-15Rα and IL-15 may lead to an autocrine cytokine-mediated stimulatory loop leading to the proliferation of HTLV-I infected cells. This loop of proliferation may facilitate viral propagation and play a role in HTLV-I-mediated disease progression.