Estradiol Represses Human T-cell Leukemia Virus Type 1 Tax Activation of Tumor Necrosis Factor-α Gene Transcription*

Abstract

Adult T-cell leukemia is caused by human T-cell leukemia virus type I (HTLV-I). The HTLV-I Tax protein is essential for clinical manifestations because it activates viral and cellular gene transcription. Tax enhances production of tumor necrosis factor-α (TNF-α), which may lead to bone and joint destruction. Because estrogens might prevent osteoporosis by repressing TNF-α gene transcription, we investigated whether estrogens inhibit the transcriptional effects of Tax on the TNF-α promoter. Tax activated the −1044, −163, and −125 TNF-α promoters by 9–25-fold but not the −82 promoter, demonstrating that Tax activation requires the −125 to −82 region, known as the TNF response element (TNF-RE). Three copies of the TNF-RE upstream of the minimal thymidine kinase promoter conferred a similar magnitude of activation by Tax. We demonstrated that c-Jun, NFκB, p50, and p65 interact with and activate the TNF-RE by using mutational analysis of the TNF-RE, Tax mutants that selectively activate NFκB or the cAMP-response element binding protein/activating transcription factor pathway, and gel shift assays with nuclear extracts. Estradiol markedly repressed Tax-activated transcription of the TNF-α gene with estrogen receptor (ER) α or β. Nuclear extracts from U2OS cells stably transfected with ERα demonstrated that ERs interact with the TNF-RE. Our studies provide evidence that ERs repress Tax-activatedTNF-α transcription by interacting with a c-Jun and NFκB platform on the TNF-RE. Estrogens may ameliorate bone and inflammatory joint diseases in patients infected with HTLV-I by repressing transcription of the TNF-α gene.