Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: Attenuation by 17β-estradiol

Annadora J. Bruce-Keller, Steven W. Barger, Naeeta I. Moss, Jaqueline T. Pham, Jeffrey N. Keller, Avindra Nath

Research output: Contribution to journalArticlepeer-review

Abstract

Microglia are activated in humans following infection with human immunodeficiency virus (HIV), and brain inflammation is thought to be involved in neuronal injury and dysfunction during HIV infection. Numerous studies indicate a role for the HIV regulatory protein Tat in HIV-related inflammatory and neurodegenerative processes, although the specific effects of Tat on microglial activation, and the signal transduction mechanisms thereof, have not been elucidated. In the present study, we document the effects of Tat on microglial activation and characterize the signal transduction pathways responsible for Tat's pro-inflammatory effects. Application of Tat to N9 microglial cells increased multiple parameters of microglial activation, including superoxide production, phagocytosis, nitric oxide release and TNFα release. Tat also caused activation of both p42/p44 mitogen activated protein kinase (MAPK) and NFκB pathways. Inhibitor studies revealed that Tat-induced NFκB activation was responsible for increased nitrite release, while MAPK activation mediated superoxide release, TNFα release, and phagocytosis. Lastly, pre-treatment of microglial cells with physiological concentrations of 17β-estradiol suppressed Tat-mediated microglial activation by interfering with Tat-induced MAPK activation. Together, these data elucidate specific components of the microglial response to Tat and suggest that Tat could contribute to the neuropathology associated with HIV infection through microglial promulgation of oxidative stress.

Original languageEnglish (US)
Pages (from-to)1315-1324
Number of pages10
JournalJournal of Neurochemistry
Volume78
Issue number6
DOIs
StatePublished - 2001

Keywords

  • AIDS-associated dementia
  • Human immunodeficiency virus
  • Inflammation
  • Microglia
  • Phagocytosis
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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