HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes

The mechanism whereby HIV-infected cells transit from the bloodstream into tissues is not well defined. This phenomenon was addressed by studying the effects of HIV-1 Tat, a protein secreted by infected cells, on human lung m icrovascular endothelial cells (HMVEC-Ls). It was found that monocyte chemo attractant protein-1 (MCP-I) was released from HMVEC-Ls in a dose- and time -dependent manner after Tat treatment. MCP-1 is a potent beta -chemokine th at recruits monocytes and T cells and promotes cell adhesion and transmigra tion across an endothelial monolayer. It was also observed that MCP-1 and t he culture medium from Tat-treated HMVEC-Ls were chemotactic for CD14(+) mo nocytes from human peripheral blood and for THP-1, a promonocytic cell line used as a model system. To characterize the signaling pathways underlying the observed induction of MCP-1, HMVEC-Ls were treated with 2 different pro tein kinase inhibitors: PD98059, a MAP kinase inhibitor, and GF109203X, a p rotein kinase C (PKC) inhibitor. MCP-1 release was significantly reduced wh en PKC was inhibited, and slightly decreased when PI3 kinase was blocked; n o effect on MCP-1 release was observed on MAP kinase inhibition. Similarly transmigration of THP-I cells was significantly impaired by the PKC inhibit or, but not by the other tested inhibitors. These data indicate that the HI V-1 Tat protein may act as a protocytokine by causing the release of MCP-1 from the endothelial monolayer, and thereby facilitating monocyte transmigr ation into tissues via a PKC signaling pathway. (C) 2001 by The American So ciety of Hematology.