title: Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia.
abstract: Human immunodeficiency virus (HIV) infection is commonly associated with neurological disease that occurs in the apparent absence of extensive infection of brain cells by HIV, suggesting that indirect mechanisms account for neuropathogenesis in the CNS, perhaps including changes in the normal neuroprotective functions of astrocytes. To test this hypothesis, we examined the effect of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha), produced by HIV-1-infected macrophages and microglia, on glutamate transport by primary human fetal astrocytes (PHFAs). A dose-dependent inhibition of high affinity glutamate uptake sites was observed 12-24 h after addition of exogenous recombinant human TNFalpha to PHFAs. This effect was specific since it was blocked by a neutralizing monoclonal antibody directed against TNFalpha. Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that is an agonist at the 55-kDa TNF receptor. These results suggest that the neurotoxic effects of TNFalpha may be due in part to its ability to inhibit glutamate uptake by astrocytes, which in turn may result in excitotoxic concentrations of glutamate in synapses.
authors.affiliation: Department of Medicine (Infectious Diseases), University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Fine
authors.forename: R A
authors.initials: RA
authors.lastname: Angel
authors.forename: S W
authors.initials: SW
authors.lastname: Perry
authors.forename: L G
authors.initials: LG
authors.lastname: Epstein
authors.forename: J D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
authors.forename: H A
authors.initials: HA
authors.lastname: Gelbard
mesh_terms: D015526:AIDS Dementia Complex / Q000209:etiology*; D001253:Astrocytes / Q000378:metabolism*; D001692:Biological Transport; D002478:Cells, Cultured; D005333:Fetus; D005971:Glutamates / Q000378:metabolism*; D015658:HIV Infections / Q000503:physiopathology; D006801:Humans; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D005971:Glutamates; D014409:Tumor Necrosis Factor-alpha