title: IFN regulatory factor 4 participates in the human T cell lymphotropic virus type I-mediated activation of the IL-15 receptor alpha promoter.
abstract: IL-15Ralpha 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-15Ralpha expression was activated by HTLV-I Tax, in part, through the action of NF-kappaB. However, there appeared to be additional motifs within the IL-15Ralpha promoter that were responsive to HTLV-I Tax. In this study, we demonstrated that IL-15Ralpha mRNA expression was activated in human monocytes by IFN treatment, suggesting a role for IFN regulatory factors (IRFs) in IL-15Ralpha transcription. In addition, an IRF element within the Tax-responsive element of the IL-15Ralpha 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-15Ralpha promoter. Inhibition of IRF-4 action lead to reduced Tax-induced activation of the IL-15Ralpha promoter, while inhibition of both IRF-4 and NF-kappaB severely inhibited the Tax-induced activation of this promoter. These findings suggest a role for both NF-kappaB and IRF-4 in the transcriptional regulation of IL-15Ralpha by HTLV-I Tax. It is possible that the HTLV-I Tax-mediated induction of IL-15Ralpha 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.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mariner
authors.forename: Yael
authors.initials: Y
authors.lastname: Mamane
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Nazli
authors.initials: N
authors.lastname: Azimi
mesh_terms: D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000494:pharmacology; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors; D007372:Interferons / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D020218:Response Elements; D014157:Transcription Factors / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D050835:Interferon Regulatory Factors; D007372:Interferons; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C508024:IL15RA protein, human