RANTES-induced chemokine cascade in dendritic cells.
Dendritic cells (DC) are the most potent APCs and the principal activators of naive T cells. We now report that chemokines can serve as activating agents for immature DC. Murine bone marrow-derived DC respond to the CC chemokine RANTES (10-100 ng/ml) by production of proinflammatory mediators. RANTES induces rapid expression of transcripts for the CXC chemokines KC and macrophage inflammatory protein (MIP)-2, the CC chemokines MIP-1beta and MIP-1alpha, and the cytokines TNF-alpha and IL-6. Synthesis of KC, IL-6, and TNF-alpha proteins were also demonstrated. After 4 h, autoinduction of RANTES transcripts was observed. These responses are chemokine specific. Although DC demonstrated weak responses to eotaxin, DC failed to respond to other chemokines including KC, MIP-2, stromal-derived factor-1alpha, MIP-1beta, MIP-1alpha, monocyte chemoattractant protein-1, T cell activation gene 3, or thymus-derived chemotactic agent 4. In addition, RANTES treatment up-regulated expression of an orphan chemokine receptor termed Eo1. Chemokine induction was also observed after treatment of splenic DC and neonatal microglia with RANTES, but not after treatment of thymocytes or splenocytes depleted of adherent cells. TNF-alpha-treated DC lose responsiveness to RANTES. DC from mice deficient for CCR1, CCR3, and CCR5 respond to RANTES, indicating that none of these receptors are exclusively used to initiate the chemokine cascade. RANTES-mediated chemokine amplification in DC may prolong inflammatory responses and shape the microenvironment, potentially enhancing acquired and innate immune responses.
Fischer
F R
FR
Department of Pathology, Harvard Medical School, Dana Farber Cancer Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
Luo
Y
Y
Luo
M
M
Santambrogio
L
L
Dorf
M E
ME
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D019742:Chemokines, CC; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger