Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism

Glia. 1996 Mar;16(3):276-84. doi: 10.1002/(SICI)1098-1136(199603)16:3<276::AID-GLIA10>3.0.CO;2-X.


Astrocytes have been reported to play a neuropathogenic role within the brain, although little is known about the mechanism underlying astrocyte-mediated neuronal injury. We investigated the hypothesis that cytokine-stimulated astrocytes adversely affect neuronal cell survival via generation of the free radical nitric oxide (NO). Primary human astrocytes produced substantial amounts of NO in response to interleukin (IL)-1 alpha or IL-1 beta, which was blocked by the NO synthase inhibitor NG-mono-methyl-L-arginine (NMMA). IL-1 beta-induced NO production was markedly potentiated by interferon (IFN)-gamma. IL-1 receptor agonist protein (IRAP) totally blocked NO generation by cytokine-stimulated astrocytes. Using reverse transcription-polymerase chain reaction and sequencing analyses of the astrocyte NO synthase gene, we found a single band encoding for a 615 bp product that was identical to the corresponding sequence reported for human hepatocytes. Treatment of human fetal brain cell cultures with IL-1 beta plus IFN-gamma resulted in marked neuronal loss, as assessed by microscopic analysis and measurement of lactate dehydrogenase release. This cytokine-induced neuronal damage was blocked by simultaneous treatment of the brain cell cultures with NMMA or IRAP, suggesting a critical role of IL-1. These findings indicate that cytokine-stimulated astrocytes are neurotoxic via a NO-mediated mechanism and point to potential new therapies for neurodegenerative disorders that involve cytokines and reactive astrocytes.

Publication types

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

MeSH terms

  • Astrocytes / metabolism
  • Astrocytes / physiology*
  • Base Sequence
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Enzyme Induction
  • Fetus
  • Humans
  • Molecular Sequence Data
  • Neurons / pathology*
  • Nitric Oxide / metabolism
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins


  • Cytokines
  • RNA, Messenger
  • Recombinant Proteins
  • Nitric Oxide
  • Nitric Oxide Synthase