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

Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-1 alpha (IL-1 alpha), To analyze the mechanisms that lead to the expression of IL-1 alpha in HTLV-I-infected cell lines, we studied regulatory regions of the human IL-1 alpha promoter involved in activation of the IL-1 alpha gene. IL-1 alpha promoter constructs drive transcription of the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells, which constitutively produce IL-1 alpha. In a cotransfection assay, the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1 alpha promoter in an uninfected Jurkat cell line. A mutant Tax protein deficient in transactivation of genes by the nuclear factor (NF)-kappa B pathway was unable to induce transcriptional activity of IL-1 alpha promoter-CAT constructs, but was rescued by exogenous provision of p65/p50 NF-kappa B. We found that two IL-1 alpha kappa B-like sites (positions -1,065 to -1,056 and +646 to +655) specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2 cells and that NF-kappa B bound with higher affinity to the 3' NF-kappa B binding site than to the 5' NF-kappa B site. Moreover, deletion of either 5' or 3' NF-kappa B sites reduced IL-1 alpha promoter activity in MT-2 cells and transactivation of the IL-1 alpha promoter by exogenous NF-kappa B and Tax in Jurkat cells, These data suggest a general role for Tax induction of IL-1 alpha gene transcription by the NF-kappa B pathway. Expression of IL-1 alpha 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. (C) 1996 by The American Society of Hematology.