Transactivation of the interleukin-1α promoter by human T-cell leukemia virus type I and type II tax proteins

Abstract

Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-1α (IL-1α). To analyze the mechanisms that lead to the expression of IL-1α in HTLV-I-infected cell lines, we studied regulatory regions of the human IL-1α promoter involved in activation of the IL-1α gene. IL-1α promoter constructs drive transcription of the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I- positive MT-2 cells, which constitutively produce IL-1α. In a cotransfection assay, the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1α promoter in an uninfected Jurkat cell line. A mutant Tax protein deficient in transactivation of genes by the nuclear factor (NF)-κB pathway was unable to induce transcriptional activity of IL- 1α promoter-CAT constructs, but was rescued by exogenous provision of p65/p50 NF-κB. We found that two IL-1α κB-like sites (positions -1,065 to -1,056 and +646 to +655) specifically formed a complex with NF-κB-containing nuclear extract from MT-2 cells and that NF-κB bound with higher affinity to the 3' NF-κB binding site than to the 5' NF-κB site. Moreover, deletion of either 5' or 3' NF-κB sites reduced IL-1α promoter activity in MT-2 cells and transactivation of the IL-1α promoter by exogenous NF-κB and Tax in Jurkat cells. These data suggest a general role for Tax induction of IL-1α gene transcription by the NF-κB pathway. Expression of IL-1α by HTLV-I productively infected cells may be important in the hypercalcemia, osteolytic bone lesions, neutrophilia, elevation of C-reactive protein, and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma.