Modulation of astrocyte inducible nitric oxide synthase and cytokine expression by interferon β is associated with induction and inhibition of interferon γ-activated sequence binding activity

Liwei L. Hua, Mee Ohk Kim, Celia F. Brosnan, Sunhee C. Lee

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Although interferon (IFN)-β is firmly established as a therapeutic agent for multiple sclerosis, information regarding its role in astrocyte cytokine production is limited. In primary cultures of human astrocytes, we determined the effects of IFN-β on astrocyte cytokine [tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6] and inducible nitric oxide synthase (iNOS) expression by ribonuclease protection assay and ELISA. We found that IFN-β inhibited astrocyte cytokine/iNOS induced by IL-1 plus IFN-γ, but in the absence of IFN-γ, IFN-β enhanced IL-1-induced cytokine/iNOS expression. Electrophoretic mobility shift analysis (EMSA) demonstrated that IFN-γ induced sustained IFN-γ-activated sequence (GAS) binding, while IFN-β induced transient GAS binding. When used together, IFN-β inhibited IFN-γ-induced GAS binding activity. Nuclear factor-kappa B (NF-κB) activation was not altered by either IFNs, whereas IFN stimulated response element (ISRE) was only activated by IFN-β and not IFN-γ. These results suggest that IFN-β can both mimic and antagonize the effect of IFN-γ by modulating induction of nuclear GAS binding activity. Our results demonstrating differential regulation of astrocyte cytokine/iNOS induction by IFN-β are novel and have implications for inflammatory diseases of the human CNS.

Original languageEnglish (US)
Pages (from-to)1120-1128
Number of pages9
JournalJournal of Neurochemistry
Volume83
Issue number5
DOIs
StatePublished - Dec 1 2002

Keywords

  • Astrocytes
  • Human
  • Interferons
  • Nitric oxide
  • Signal transducer and activator of transcription
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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