RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes.
Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3-10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1alpha and -beta [MIP-1alpha, MIP-1beta]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), MIP-1alpha, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-alpha) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Yi
Y
Luo
Michael A
MA
Berman
Qiwei
Q
Zhai
Falko R
FR
Fischer
Sara R
SR
Abromson-Leeman
Ye
Y
Zhang
William A
WA
Kuziel
Craig
C
Gerard
Martin E
ME
Dorf
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000494:pharmacology*; D018925:Chemokines / Q000096:biosynthesis / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D037342:Pertussis Toxin; D019707:Receptors, Chemokine / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D019707:Receptors, Chemokine; D010566:Virulence Factors, Bordetella; D018799:Intercellular Adhesion Molecule-1; D037342:Pertussis Toxin