Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier

The migration of leukocytes across the blood-brain barrier (BBB) into the c entral nervous system is critical in the pathogenesis of central nervous sy stem inflammatory diseases, The production of chemokines, such as monocyte- chemoattractant protein-1 (MCP-I), by endothelial cells (EC) and astrocytes may initiate and amplify this process. Using a coculture of human EC and a strocytes to model the BBB, we demonstrated that exogenous MCP-1 induces th e transmigration of monocytes in a dose-dependent manner, TNF-alpha, IFN-ga mma, or IL-beta treatment of cocultures also induced significant migration of monocytes that correlates with the induction of MCP-I protein, TGF-beta, previously shown to induce MCP-1 expression in astrocytes, but not in EC, caused migration of monocytes across cocultures, but not across EC grown al one. Monocytes and lymphocytes transmigrated across cytokine-treated cocult ures in greater numbers than across EC alone. Astrocytes were the main sour ce of cytokine-induced MCP-1, supporting a role for astrocytes in facilitat ing leukocyte transmigration, A blocking Ab to MCP-1 inhibited MCP-1- and c ytokine-induced transmigration of monocytes by 85-90%, Cytokine treatment o f cocultures also resulted in the transmigration of activated, CD69-positiv e lymphocytes, The MCP-l-mediated transmigration of monocytes across cocult ures was blocked using an Ab to ICAM-1 and inhibited by 55% using an Ab to E-selectin, These data suggest a central role for astrocyte-derived MCP-1 i n directing the migration of monocytes and lymphocytes across the BBB.