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J. Biol. Chem., Vol. 277, Issue 42, 39312-39319, October 18, 2002
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From the Department of Oral Biology, University of Nebraska Medical
Center, Lincoln, Nebraska 68583 and the 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-
Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces
Nitric-oxide Synthase in Human Astroglia*
,, and Nebraska Center
for Virology and School of Biological Sciences, University of Nebraska,
Lincoln, Nebraska 68588
B and C/EBP
, transcription factors responsible for the
induction of iNOS. Activation of NF-B as well as C/EBP by
RSV-tat, stimulation of RSV-tat-induced
production of NO by the wild type of p65 and C/EBP, and inhibition
of RSV-tat-induced production of NO by 
p65, a
dominant-negative mutant of p65, and C/EBP, a dominant-negative
mutant of C/EBP, suggest that RSV-tat induces iNOS
through the activation of NF-B and C/EBP. 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 ERK2, a dominant-negative
mutant of ERK2, inhibited RSV-tat-induced production of NO
through the inhibition of C/EBP but not that of NF-B. 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.
*
This study was supported by Public Health Service
Grants NS39940 (to K. P.) and P20-RR15635 and CA76958 (to C. W.).
from the National Institutes of Health.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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