BIDIRECTIONAL INDUCTION OF MATRIX METALLOPROTEINASE-9 AND TISSUE INHIBITOR OF MATRIX METALLOPROTEINASE-1 DURING T-LYMPHOMA ENDOTHELIAL-CELLCONTACT - IMPLICATION OF ICAM-1

The mechanisms that lead to the expression of matrix metalloproteinase s (MMP) and tissue inhibitors of MMP (TIMPs) during the invasive proce ss of normal and transformed T cells remain largely unknown. Since vas cular cells form a dynamic tissue capable of responding to local stimu li and activating cells through the expression of cytokine receptors a nd specific cell adhesion molecules, we hypothesized that the firm adh esion of T lymphoma cells to endothelial cells is a critical event in the local production of MMP and TIMP. In the present work, we show tha t adhesion of lymphoma cells to endothelial cells induced a transient and reciprocal de novo expression of MMP-9 mRNA and enzymatic activity by both cell types, Up-regulation of MMP-9 in T lymphoma cells was co ncomitant to that of TIMP-1, and required direct contact with endothel ial cells, Induction of MMP-9, but not of TIMP-1, was blocked by anti- LFA-1 and anti-intercellular adhesion molecule-1 Abs, indicating that induction of MMP-9 and TIMP-1 in lymphoma cells required direct, yet d istinct, intercellular contact, In contrast, the induction of MMP-9 in endothelial cells by T lymphoma cells did not necessitate direct cont act and could be achieved by exposure to IL-1 and TNF, or to the super natant of T lymphoma cell culture, Together, these results demonstrate that firm adhesion of T lymphoma cells to endothelial cells participa tes in the production of MMP-9 in both cell types through bi-direction al signaling pathways, and identify intercellular adhesion molecule-1/ LFA-1 as a key interaction in the up-regulation of MMP-9 in T lymphoma cells.