Neuronal death in cytokine-activated primary human brain cell culture

Role of tumor necrosis factor-α

Martha Downen, Terry D. Amaral, Liwei L. Hua, Meng Liang Zhao, Sunhee C. Lee

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

We examined cytokine-mediated neuronal death in neuron-astrocyte cultures from second trimester human fetal cerebrum. In these cultures, high-output inducible nitric oxide synthase (NOS) and tumor necrosis factor-α (TNFα) are expressed in astrocytes after exposure to IL-1β/IFNγ. Neuronal cell death was evident at ≥48 h following cytokine stimulation. Neutralizing anti-TNFα antiserum inhibited (≃48%) neurotoxicity in IL-1β/IFNγ-treated cultures, demonstrating a role for endogenously produced TNFα. Interestingly, the degree of neuroprotection conferred by superoxide dismutase or N-methyl D-aspartate (NMDA) receptor antagonists in these cultures was smaller and variable. Similarly, the effect of the NOS inhibitor, N(G)-monomethyl L-arginine (NMMA) on IL-1β/IFNγ-induced neuronal death was variable, showing no statistically significant effect when results from more than 30 independent cultures were averaged. Neurons die by apoptosis in cytokine-treated human fetal CNS cultures as shown by the characteristic nuclear morphology as well as positive labeling for TUNEL. Our results demonstrate a potent neurotoxicity mediated by the cytokine combination IL-1β/IFNγ in primary human neuron-astrocyte cultures and a crucial role for endogenous TNFα in mediating neurotoxicity in this system. These results firmly establish the neurotoxic potential of the inflammatory cytokines IL-1β and TNFα in the human CNS.

Original languageEnglish (US)
Pages (from-to)114-127
Number of pages14
JournalGLIA
Volume28
Issue number2
DOIs
StatePublished - Nov 1999

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Interleukin-1
Cell Culture Techniques
Tumor Necrosis Factor-alpha
Cytokines
Astrocytes
Brain
Neurons
In Situ Nick-End Labeling
Cerebrum
Second Pregnancy Trimester
Nitric Oxide Synthase Type II
N-Methyl-D-Aspartate Receptors
Nitric Oxide Synthase
Superoxide Dismutase
Arginine
Immune Sera
Cell Death
Apoptosis

Keywords

  • Apoptosis
  • Glia
  • Interleukin-1β
  • Neurotoxicity
  • Nitric oxide
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Immunology

Cite this

Neuronal death in cytokine-activated primary human brain cell culture : Role of tumor necrosis factor-α. / Downen, Martha; Amaral, Terry D.; Hua, Liwei L.; Zhao, Meng Liang; Lee, Sunhee C.

In: GLIA, Vol. 28, No. 2, 11.1999, p. 114-127.

Research output: Contribution to journalArticle

Downen, Martha ; Amaral, Terry D. ; Hua, Liwei L. ; Zhao, Meng Liang ; Lee, Sunhee C. / Neuronal death in cytokine-activated primary human brain cell culture : Role of tumor necrosis factor-α. In: GLIA. 1999 ; Vol. 28, No. 2. pp. 114-127.
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