Tumor necrosis factor alpha-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells

J. Tangpong, P. Sompol, M. Vore, W. St. Clair, D. A. Butterfield, D. K. St. Clair

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Tumor necrosis factor-alpha (TNF-α), a ubiquitous pro-inflammatory cytokine, is an important mediator in the immune-neuroendocrine system that affects the CNS. The present study demonstrates that treatment with TNF-α activates microglia to increase TNF-α production in primary cultures of glial cells isolated from wild-type (WT) mice and mice deficient in the inducible form of nitric oxide synthase (iNOSKO). However, mitochondrial dysfunction in WT neurons occurs at lower concentrations of TNF-α when neurons are directly treated with TNF-α or co-cultured with TNF-α-treated microglia than iNOSKO neurons similarly treated. Immunofluorescent staining of primary neurons co-cultured with TNF-α-treated microglia reveals that the antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), is co-localized with nitrotyrosine in WT but not in iNOSKO primary neuronal cells. Importantly, the percentage of surviving neurons is significantly reduced in WT neurons compared with iNOSKO neurons under identical treatment conditions. Together, the results suggest that TNF-α activates microglia to produce high levels of TNF-α and that production of nitric oxide (NO) in neurons is an important factor affecting MnSOD nitration and subsequent mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)622-629
Number of pages8
JournalNeuroscience
Volume151
Issue number2
DOIs
StatePublished - Jan 24 2008

Bibliographical note

Funding Information:
This work is supported, in part, by NIH grants to D.K.S.C. [AG-05119, CA-80152, and CA-94853].

Keywords

  • CNS toxicity
  • MnSOD nitration
  • iNOSKO
  • mitochondrial dysfunction
  • nitric oxide
  • tumor necrosis factor-alpha

ASJC Scopus subject areas

  • General Neuroscience

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