Proteasome blockers inhibit TNF-α release by lipopolysaccharide stimulated macrophages and microglia: Implications for HIV-1 dementia

Steven M. Fine*, Sanjay B. Maggirwar, Paige R. Elliott, Leon G. Epstein, Harris A. Gelbard, Stephen Dewhurst

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

HIV-1 infection of the central nervous system can cause severe neurologic disease although only microglial cells and brain macrophages are susceptible to productive viral infection. Substances secreted by infected cells are thought to cause disease indirectly. Tumor necrosis factor alpha (TNF-α) is one candidate neurotoxin and is upregulated during HIV-1 infection of the brain, likely via activation of the transcription factor NF- κB. We used the proteasome inhibitors, MG132 and ALLN (N-acetyl-Leu-Leu- Norleucinal), to inhibit NF-κB activation in primary human fetal microgila (PHFM) and primary monocyte derived-macrophages, and showed that they could block TNF-α release stimulated by lipopolysaccharide (LPS) or TNF-α. In addition, we performed electrophoretic mobility shift analysis and determined that in microglia, the p50/p65 heterodimer of NF-κB is activated by LPS stimulation, and is inhibited by MG132. Thus, blockade of NF-κB activation in microglia in vitro can decrease production of TNF-α and may prove to be a novel strategy for treating HIV-1 dementia.

Original languageEnglish (US)
Pages (from-to)55-64
Number of pages10
JournalJournal of Neuroimmunology
Volume95
Issue number1-2
DOIs
StatePublished - Mar 1 1999

Keywords

  • Human immunodeficiency virus type 1
  • Lipopolysaccharide
  • Macrophage
  • Microglia
  • NF-κB
  • Proteasome inhibitor
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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