TY - JOUR
T1 - Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier
AU - Weiss, Jonathan M.
AU - Downie, Sherry A.
AU - Lyman, William D.
AU - Berman, Joan W.
PY - 1998/12/15
Y1 - 1998/12/15
N2 - The migration of leukocytes across the blood-brain barrier (BBB) into the central nervous system is critical in the pathogenesis of central nervous system inflammatory diseases. The production of chemokines, such as monocyte- chemoattractant protein-1 (MCP-1), by endothelial cells (EC) and astrocytes may initiate and amplify this process. Using a coculture of human EC and astrocytes to model the BBB, we demonstrated that exogenous MCP-1 induces the transmigration of monocytes in a dose-dependent manner. TNF-α, IFN-γ, or IL-1β treatment of cocultures also induced significant migration of monocytes that correlates with the induction of MCP-1 protein. TGF-β, previously shown to induce MCP-1 expression in astrocytes, but not in EC, caused migration of monocytes across cocultures, but not across EC grown alone. Monocytes and lymphocytes transmigrated across cytokine-treated cocultures in greater numbers than across EC alone. Astrocytes were the main source of cytokine-induced MCP-1, supporting a role for astrocytes in facilitating leukocyte transmigration. A blocking Ab to MCP-1 inhibited MCP- 1- and cytokine-induced transmigration of monocytes by 85-90%. Cytokine treatment of cocultures also resulted in the transmigration of activated, CD69-positive lymphocytes. The MCP-1-mediated transmigration of monocytes across cocultures 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 in directing the migration of monocytes and lymphocytes across the BBB.
AB - The migration of leukocytes across the blood-brain barrier (BBB) into the central nervous system is critical in the pathogenesis of central nervous system inflammatory diseases. The production of chemokines, such as monocyte- chemoattractant protein-1 (MCP-1), by endothelial cells (EC) and astrocytes may initiate and amplify this process. Using a coculture of human EC and astrocytes to model the BBB, we demonstrated that exogenous MCP-1 induces the transmigration of monocytes in a dose-dependent manner. TNF-α, IFN-γ, or IL-1β treatment of cocultures also induced significant migration of monocytes that correlates with the induction of MCP-1 protein. TGF-β, previously shown to induce MCP-1 expression in astrocytes, but not in EC, caused migration of monocytes across cocultures, but not across EC grown alone. Monocytes and lymphocytes transmigrated across cytokine-treated cocultures in greater numbers than across EC alone. Astrocytes were the main source of cytokine-induced MCP-1, supporting a role for astrocytes in facilitating leukocyte transmigration. A blocking Ab to MCP-1 inhibited MCP- 1- and cytokine-induced transmigration of monocytes by 85-90%. Cytokine treatment of cocultures also resulted in the transmigration of activated, CD69-positive lymphocytes. The MCP-1-mediated transmigration of monocytes across cocultures 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 in directing the migration of monocytes and lymphocytes across the BBB.
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M3 - Article
C2 - 9862722
AN - SCOPUS:0032534571
SN - 0022-1767
VL - 161
SP - 6896
EP - 6903
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -