Abstract
Following antigen acquisition and maturation, dendritic cells (DCs) disengage from the extracellular matrix, cross basement membranes, and travel to draining lymph nodes to activate T cells. CCR7 expression is necessary but not sufficient for the directional migration of DCs. Prostaglandin E2 (PGE2), present in inflammatory sites, induces DC migration, presumably by enacting a migration-permissive gene expression program. Since regulation of DC migration is highly important for their use in vaccination and therapy, we examined the PGE2-induced changes in the expression of metalloproteinases (MMPs). Our results indicate that PGE2 significantly up-regulates MMP-9 expression, induces both secreted and membrane-bound MMP-9, and that in turn, DC-derived MMP-9 is essential for DC chemotaxis in response to the CCR7 ligand CCL19, Matrigel migration, and in vivo migration in both wild-type and MMP-9-deficient hosts. We conclude that DCs matured within inflammatory sites require both CCR7 and PGE2-induced MMP-9 for their directional migration to draining lymph nodes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Membrane / enzymology
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Cell Movement / drug effects
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Cell Movement / immunology*
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Chemokine CCL19 / metabolism
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Collagen
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Dendritic Cells / cytology*
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Dendritic Cells / enzymology*
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Dinoprostone / metabolism*
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Dinoprostone / pharmacology
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Drug Combinations
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / immunology
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Interferon-gamma / pharmacology
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Laminin
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Matrix Metalloproteinase 9 / genetics*
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Mutant Strains
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Proteoglycans
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RNA, Messenger / metabolism
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Receptors, Prostaglandin E / metabolism
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Chemokine CCL19
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Drug Combinations
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Laminin
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Proteoglycans
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Ptger2 protein, mouse
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Ptger4 protein, mouse
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RNA, Messenger
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Tumor Necrosis Factor-alpha
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matrigel
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Interferon-gamma
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Collagen
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Matrix Metalloproteinase 9
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Dinoprostone