title: Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier.
abstract: 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-alpha, IFN-gamma, or IL-1beta treatment of cocultures also induced significant migration of monocytes that correlates with the induction of MCP-1 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 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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. weiss@aecom.yu.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Weiss
authors.forename: S A
authors.initials: SA
authors.lastname: Downie
authors.forename: W D
authors.initials: WD
authors.lastname: Lyman
authors.forename: J W
authors.initials: JW
authors.lastname: Berman
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001253:Astrocytes / Q000502:physiology*; D001812:Blood-Brain Barrier; D002450:Cell Communication; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D018920:Coculture Techniques; D019040:E-Selectin / Q000276:immunology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D000099192:CD69 Antigens
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018932:Chemokine CCL2; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D007375:Interleukin-1; D037181:Lectins, C-Type; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens