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

Mee Ohk Kim, Hyeon Sook Suh, Celia F. Brosnan, Sunhee C. Lee

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)297-308
Number of pages12
JournalJournal of Neurochemistry
Volume90
Issue number2
DOIs
Publication statusPublished - Jul 1 2004

    Fingerprint

Keywords

  • Brain
  • Chemokine
  • Human
  • Promoter
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this