Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia

Xiaojuan Liu, Malabendu Jana, Subhajit Dasgupta, Sreenivas Koka, Jun He, Charles Wood, Kalipada Pahan

Research output: Contribution to journalArticle

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Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia. Expression of the tat gene as RSV-tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV-tat-induced NO production by anti-Tat antibodies suggest that RSV-tat-induced production of NO is dependent on Tat and that Tat is secreted from RSV-tat-transfected astroglia. Similar to U373MG astroglial cells, RSV-tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity by the expression of RSV-tat suggests that RSV-tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-κB and C/EBPβ, transcription factors responsible for the induction of iNOS. Activation of NF-κB as well as C/EBPβ by RSV-tat, stimulation of RSV-tat-induced production of NO by the wild type of p65 and C/EBPβ, and inhibition of RSV-tat-induced production of NO by Δp65, a dominant-negative mutant of p65, and ΔC/EBPβ, a dominant-negative mutant of C/EBPβ, suggest that RSV-tat induces iNOS through the activation of NF-κB and C/EBPβ. In addition, we show that extracellular signal-regulated kinase (ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV-tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and ΔERK2, a dominant-negative mutant of ERK2, inhibited RSV-tat-induced production of NO through the inhibition of C/EBPβ but not that of NF-κB. This study illustrates a novel role for HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia.

Original languageEnglish (US)
Pages (from-to)39312-39319
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number42
DOIs
StatePublished - Oct 18 2002

Fingerprint

Nitric Oxide Synthase Type II
Viruses
Nitric Oxide Synthase
Astrocytes
HIV-1
tat Genes
Extracellular Signal-Regulated MAP Kinases
Genes
tat Gene Products
AIDS Dementia Complex
Chemical activation
p38 Mitogen-Activated Protein Kinases
Virus Diseases
Luciferases
Transcription
Dementia
Anti-Idiotypic Antibodies
Transcription Factors
Brain
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. / Liu, Xiaojuan; Jana, Malabendu; Dasgupta, Subhajit; Koka, Sreenivas; He, Jun; Wood, Charles; Pahan, Kalipada.

In: Journal of Biological Chemistry, Vol. 277, No. 42, 18.10.2002, p. 39312-39319.

Research output: Contribution to journalArticle

Liu, Xiaojuan ; Jana, Malabendu ; Dasgupta, Subhajit ; Koka, Sreenivas ; He, Jun ; Wood, Charles ; Pahan, Kalipada. / Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 42. pp. 39312-39319.
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