TRANSCRIPTIONAL ACTIVATION OF THE VASCULAR CELL-ADHESION MOLECULE-1 GENE IN T-LYMPHOCYTES EXPRESSING HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 TAXPROTEIN

Recruitment and extravasation of T cells through the blood-brain barri er are favored by adhesion molecule-mediated interactions of circulati ng T cells with endothelial cells, Since a common pathological finding in human T-cell leukemia virus type 1 (HTLV-1)-associated diseases is the infiltration of HTLV-1-infected T lymphocytes into various organs , we have looked for the profile of adhesion molecules expressed by HT LV-1-transformed T cells, Flow cytometry analysis indicated that these cells were expressing high levels of vascular cell adhesion molecule 1 (VCAM-1 [CD106]), a 110-kDa member of the immunoglobulin gene superf amily, first identified on endothelial cells stimulated with inflammat ory cytokines, This adhesion molecule was also expressed by T cells ob tained from one patient with HTLV-1-associated myelopathy/tropical spa stic paraparesis but not by activated T cells isolated from one normal blood donor, The role of the viral trans-activator Tax protein in the induction of VCAM-1 was first indicated by the detection of this adhe sion molecule on Jurkat T-cell clones stably expressing the tax gene, The effect of Tax on VCAM-1 gene transcription was next confirmed in J PX-9 cells, a subclone of Jurkat cells, carrying the tax sequences und er the control of an inducible promoter, Furthermore, deletion and mut ation analyses of the VCAM-1 promoter performed with chloramphenicol a cetyltransferase constructs revealed that Tax was trans activating the VCAM-1 promoter via two NF-kappa B sites present at bp - 72 and -57 i n the VCAM-1 gene promoter, with both of them being required for the T ax-induced expression of this adhesion molecule, Finally, gel mobility shift assays demonstrated the nuclear translocation of proteins speci fically bound to these two NF-kappa B motifs, confirming that VCAM-1 w as induced on Tax-expressing cells in a kappa B-dependent manner, Coll ectively, these results therefore suggest that the exclusive Tax-induc ed expression of VCAM-1 on T cells may represent a pivotal event in th e progression of HTLV-1-associated diseases.