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Human T-Cell Leukemia Virus Type I Tax Activates Transcription of the Human Monocyte Chemoattractant Protein-1 Gene through Two Nuclear Factor-B Sites

Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan [N. M., N. Y.]; Department of Laboratory Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan [Y. Yamad.]; Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan [M. T.]; Department of Internal Medicine, City of Sasebo General Hospital, Sasebo 857-8511, Japan [S. I.]; Department of Internal Medicine, Kokura Memorial Hospital, Kitakyushu 802-8555, Japan [Y. Yamas.]; Department of Pathology First Unit, Shimane Medical University, Izumo 693-8501, Japan [S. M.]; First Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama 236-0004, Japan [A. U.]; Gladstone Institute of Virology and Immunology, San Francisco, California 94141-9100 [R. G.]; and Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [T. Y.]

Infection by human T-cell leukemia virus type (HTLV) I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis. Leukocytes are attracted to sites of inflammation by chemokines. One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines. We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia. The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-B sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-B binding to both MCP-1 B sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-B. Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases.

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