Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-κB sites

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)-kappa 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-kappa B binding to both MCP-1 kappa B sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappa 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.