title: CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities.
abstract: Although chemokines are well known to function in chemotaxis, additional roles for these molecules in the immune system are not well understood. Dendritic cells (DCs) developmentally regulate the expression of chemokine receptors to facilitate their migration from the peripheral tissues to regional lymph nodes. Expressions of CCR1 and CCR5 on immature DCs are down-regulated on maturation, whereas CCR7 is selectively expressed on mature DCs. In the present study, we examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of fluorescein isothiocyanate (FITC)-dextran by murine DCs. Both CCL19 and CCL21 markedly induced rapid uptake of FITC-dextran by mature DCs but not immature DCs. In contrast, CCL3, a ligand of CCR1 and CCR5, induced rapid uptake of FITC-dextran by immature DCs but not mature DCs. CCL19-induced endocytosis could be completely blocked by Clostridium difficile toxin B, which inhibits the Rho guanosine triphosphatase proteins, Rho, Rac, and Cdc42. This process was not abrogated by Y-27632, a specific inhibitor of Rho-associated kinase. In addition, CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs. These findings demonstrate that certain chemokines induce rapid endocytosis in each relevant DC population. It is suggested that CCR7 ligands activate Cdc42 and Rac, thereby inducing the endocytosis in mature DCs.
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Onoé
mesh_terms: D000418:Albumins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D002460:Cell Line; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000494:pharmacology; D003713:Dendritic Cells / Q000378:metabolism*; D003911:Dextrans / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000378:metabolism; D008351:Mannans / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000418:Albumins; D000577:Amides; D001426:Bacterial Proteins; D001427:Bacterial Toxins; C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D003911:Dextrans; D008351:Mannans; D011725:Pyridines; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C015219:fluorescein isothiocyanate dextran; C031815:toxB protein, Clostridium difficile; C108830:Y 27632; D037342:Pertussis Toxin; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D016650:Fluorescein-5-isothiocyanate