Regulation of RANTES/CCL5 expression in human astrocytes by interleukin‐1 and interferon‐β

• Published in: Journal of neurochemistry Vol. 90; no. 2; pp. 297 - 308
• Main Authors: Kim, Mee‐Ohk, Suh, Hyeon‐Sook, Brosnan, Celia F., Lee, Sunhee C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.07.2004; Blackwell
• Subjects: Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; brain; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Nucleus - metabolism; Cells, Cultured; chemokine; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Chemokines, CC - genetics; Chemokines, CC - metabolism; Drug Synergism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Gene Expression Regulation - physiology; Genes, Reporter; human; Humans; Interferon-beta - pharmacology; Interferon-beta - physiology; Interleukin-1 - pharmacology; Interleukin-1 - physiology; Isolated neuron and nerve. Neuroglia; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases; promoter; Response Elements - physiology; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Signal Transduction - physiology; transcription; Vertebrates: nervous system and sense organs; Human; Phosphorylation; Extracellular signal-regulated protein kinase; transcription; Enzyme; RANTES; Stress-activated kinase; Neuroglia; Cytokine; Central nervous system; Mitogen-activated protein kinase; Astrocyte; Gene expression; brain; terminal kinase; Encephalon; Chemokine; CCR5 chemokine receptor; Signal transduction; Interleukin 1; c-Jun NH; promoter; Transcription factor C/EBP; Gamma interferon
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02487.x

In the CNS, astrocytes are significant sources of RANTES/CCL5 (regulated upon activation, normal T cell expressed and secreted), a CC‐chemokine with important biological function. Astrocyte RANTES/CCL5 has been shown to be induced by interleukin‐1 (IL‐1), with interferon‐γ (IFNγ) as a primer, but whether type I interferons play any role in the expression of RANTES/CCL5 is not known. In this report, we studied the detailed mechanism of RANTES/CCL5 induction in primary human astrocytes activated with IL‐1 and IFNβ. Ribonuclease protection assay and ELISA showed that IFNβ, although not effective alone, increased IL‐1‐induced RANTES/CCL5 expression, but did not antagonize IFNγ. IL‐1 or IL‐1/IFNβ‐induced RANTES/CCL5 expression was inhibited by the super‐repressor IκBα or inhibitors of p38 or c‐Jun N‐terminal kinase (JNK) MAPKs (mitogen‐activated protein kinases), but not by extracellular signal regulated kinases (ERK) inhibitors. IFNβ enhanced IL‐1‐induced phosphorylation of p38 MAPK, but was not effective alone. Transfection with mutated RANTES/CCL5 promoter‐reporter constructs revealed that κB, interferon‐stimulated response element (ISRE) and CAATT‐enhancer binding protein‐β (C/EBPβ) sites all contributed to IL‐1/IFNβ‐induced RANTES/CCL5 transcription. IFNβ synergized with IL‐1 to induce nuclear accumulation of C/EBPβ protein. They also synergized to form nuclear ISRE complexes with Stat1, Stat2 and interferon regulatory factor‐1 (IRF‐1) proteins. Together, our results demonstrate that IFNβ plays a positive regulatory role in the expression of RANTES/CCL5 in human astrocytes through several distinct mechanisms.