RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes

Abstract

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.

CCR5 Regulates High Dose Oral Tolerance by Modulating CC Chemokine Ligand 2 Levels in the GALT

“…The results suggested that CCL2 suppressed IL-12 and augmented TGF-␤ expression in GALT-derived APCs after Ag feeding. Regulation of CCL2 by CCL5 (RANTES) has been demonstrated in astrocyte cultures (24). In the present study, we found that CCR5, the receptor for CCL3 (MIP-1␣), CCL4 (MIP-1␤), and CCL5, is essential to the induction of oral tolerance, and that the lack of oral tolerance seen in CCR5 Ϫ/Ϫ mice is related to CCL5 regulation of CCL2 expression.…”

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

“…Expression of RANTES in astrocytes and endothelial cells is stimulated by inflammatory cytokines like TNF-␣ (Croitoru-Lamoury et al, 2003;Hillyer et al, 2003). Conversely, RANTES can also increase the expression of TNF-␣ from astrocytes (Luo et al, 2002). Here we show that RANTES mRNA and TNF-␣ mRNA and protein were increased in hippocampal tissue were significantly increased when LPS-treated astrocytes were cocultured in the presence of endothelial cells (*p Ͻ 0.05; ***p Ͻ 0.001; ANOVA; n ϭ 6 per group) but this effect was attenuated when LPS-treated astrocytes were cocultured in the presence of endothelial cells that were pretreated with rosiglitazone ( ϩ p Ͻ 0.05; ϩϩ p Ͻ 0.01; ANOVA; n ϭ 6 per group).…”

Synergistic increases in intracellular Ca2+, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

“…The CC chemokines MCP-1 and RANTES, which are major attractants for monocyte/macrophage entry into the CNS and key initiators of proinflammatory cascades (Luo et al, 2002a), have been found in the brain tissue and cerebrospinal fluid of patients with HIV-1 encephalitis and AIDS dementia complex (Kelder et al, 1998;McManus et al, 2000). Although the cytokine array is sensitive and can reportedly detect protein levels as low as 4 pg/ml (compared to 40 pg/ml with ELISA), we did not see increases in TNF-α release at 4 or 12 h. Increases in TNF-α were anticipated because Tat has been previously reported to increase TNF-α expression in astrocytes (Chen et al, 1997) and TNF-α can induce the expression of IL-6 (Norris et al, 1994), MCP-1 (Oh et al, 1999;Luo et al, 2003), and RANTES (Oh et al, 1999;Meeuwsen et al, 2003) in human and/or mouse astrocytes.…”