Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

• Published in: The Journal of immunology (1950) 2004-11, Vol.173 (9), p.5458-5466
• Main Authors: Baratelli, Felicita E, Heuze-Vourc'h, Nathalie, Krysan, Kostyantyn, Dohadwala, Mariam, Riedl, Karen, Sharma, Sherven, Dubinett, Steven M
• Format: Article
• Language: English
• Subjects: 16,16-Dimethylprostaglandin E2 - metabolism; 16,16-Dimethylprostaglandin E2 - pharmacology; Adjuvants, Immunologic - metabolism; Adjuvants, Immunologic - pharmacology; Adjuvants, Immunologic - physiology; Cell Differentiation - immunology; Cell Line, Tumor; Cell Migration Inhibition; Cell Movement - immunology; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - enzymology; Dendritic Cells - metabolism; Dinoprostone - metabolism; Dinoprostone - physiology; Dose-Response Relationship, Immunologic; Extracellular Matrix - enzymology; Extracellular Matrix - immunology; Humans; Matrix Metalloproteinase 9 - metabolism; Receptors, CCR7; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - biosynthesis; Receptors, Prostaglandin E - physiology; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction - immunology; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transfection; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.9.5458

Dendritic cell (DC) migration is crucial for the initiation of immune responses. The balance between metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration. PGE2, which is overproduced in a wide variety of human malignancies, has been implicated in MMP and TIMP regulation in various cells, including monocytes. In the present study, we hypothesized that tumor-derived PGE2 would affect DC migratory capacity through the extracellular matrix (ECM) by altering MMP and TIMP balance. Treatment of monocyte-derived immature DC with exogenous PGE2 induced TIMP-1 secretion but not MMP-9 production and was correlated with reduced DC migration through ECM. Because recombinant TIMP-1 replicated PGE2 inhibition of DC migration while anti-TIMP-1 neutralizing Ab reversed it, we conclude that PGE2-mediated induction of TIMP-1 was responsible for the reduced migration of PGE2-treated DC. Similarly, DC cultured for 48 h in supernatants from cyclooxygenase-2 overexpressing lung cancer cells that secrete high levels of PGE2, exhibited decreased migration through ECM. Finally, analysis of E prostanoid receptor expression and their selective inhibition revealed that the enhanced TIMP-1 secretion in PGE2-treated DC was mediated predominantly by the E prostanoid receptor 2. These findings indicate that PGE2-dependent enhancement of TIMP-1 production causes reduced migration of DC through ECM.