Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta

J Neurochem. 2004 Jul;90(2):297-308. 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-gamma (IFNgamma) 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 IFNbeta. Ribonuclease protection assay and ELISA showed that IFNbeta, although not effective alone, increased IL-1-induced RANTES/CCL5 expression, but did not antagonize IFNgamma. IL-1 or IL-1/IFNbeta-induced RANTES/CCL5 expression was inhibited by the super-repressor IkappaBalpha 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. IFNbeta enhanced IL-1-induced phosphorylation of p38 MAPK, but was not effective alone. Transfection with mutated RANTES/CCL5 promoter-reporter constructs revealed that kappaB, interferon-stimulated response element (ISRE) and CAATT-enhancer binding protein-beta (C/EBPbeta) sites all contributed to IL-1/IFNbeta-induced RANTES/CCL5 transcription. IFNbeta synergized with IL-1 to induce nuclear accumulation of C/EBPbeta 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 IFNbeta plays a positive regulatory role in the expression of RANTES/CCL5 in human astrocytes through several distinct mechanisms.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chemokine CCL5 / genetics*
  • Chemokine CCL5 / metabolism
  • Chemokines, CC / genetics*
  • Chemokines, CC / metabolism
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Gene Expression Regulation / physiology*
  • Genes, Reporter
  • Humans
  • Interferon-beta / pharmacology
  • Interferon-beta / physiology*
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • 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
  • RNA, Messenger / metabolism
  • Response Elements / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Signal Transduction / physiology
  • p38 Mitogen-Activated Protein Kinases


  • CCAAT-Enhancer-Binding Protein-beta
  • CCL5 protein, human
  • Chemokine CCL5
  • Chemokines, CC
  • Enzyme Inhibitors
  • Interleukin-1
  • NF-kappa B
  • RNA, Messenger
  • Interferon-beta
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases