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(Received for publication, May 29, 1997, and in revised form, July 3, 1997)
From the Department of ABSTRACT Human immunodeficiency virus (HIV) infection may
cause a dementing illness. HIV-mediated dementia is clinically and
pathologically correlated with the infiltration of activated
macrophages and elevated levels of tumor necrosis factor (TNF)- INTRODUCTION Studies of neurological complications of
HIV1 infection such as
dementia, myelopathy, and neuropathy suggest an important pathogenic role for macrophage infiltration and glial cell activation. In fact,
the infection of the brain is limited compared with the severity of
clinical presentation, while macrophage infiltration and activation
most closely corelate with neuronal cell loss and the severity of
dementia (1, 2). Soluble products released from these cells have been
implicated in producing neurotoxicity (3). One such substance is a
cytokine called TNF- The Tat protein of HIV-1 is a potent transactivator of viral
replication as well as a transactivator of some host genomes. Tat is
actively released from HIV-infected cells (18, 19) and may act on
uninfected brain-derived cells to cause a variety of effects, including
activation of NF- EXPERIMENTAL PROCEDURES The human
astrocytoma cell line U373 and monocytic cell line THP-1 were obtained
from American Type Culture Collection (Rockville, MD). Human peripheral
blood mononuclear cells (PBMC) were obtained from healthy volunteers,
and whole PBMC and macrophage cultures were prepared as described
previously (28). Human fetal astrocyte cultures were prepared from
human fetal brain specimens of 12-17 weeks gestation (31). U373 cells
and astrocyte cultures were maintained in minimal essential medium with
heat-inactivated 10% (v/v) FBS. The PBMC and macrophages cells were
cultured in complete RPMI 1640 medium with 15% FBS. THP-1 cells were
cultured in RPMI medium with 10% FBS and 5.5 µM
Highly purified (>95%) recombinant
Tat protein was prepared from the tat gene encoding the
first 72 amino acids as outlined previously (21), and the functional
properties of this protein were confirmed using a transactivation assay
in HL3T1 cells containing the HIV-1 long terminal repeat,
chloramphenicol acetyltransferase construct (21). To establish dose
profiles of each cell type, Tat was used at 0, 10, 100, and 1000 nM concentrations for 4 h or 1 h for U373 cells and
astrocytes. For time course experiments in PBMC, macrophages, and THP-1
cells, Tat was used at 100 nM concentration, and for U373
cells and astrocytes, Tat was used at 1000 nM concentration
for 0, 1, 2, 4, 6, 12, 24, and 48 h. Cells were stimulated with
LPS from Escherichia coli type 055:B5 (Sigma) 1.0 µg/ml as
positive controls. Negative controls included mock (PBS)-treated cells
and cells that were treated with either solutions from which Tat had
been immunoadsorbed or Tat had been digested with trypsin followed by
inactivation with a trypsin inhibitor as described previously (24,
25).
Total
cellular RNA was prepared as described previously (32) from which first
strand cDNA was synthesized as per the manufacturer's protocol
(Pharmacia Biotech Inc.). PCR was conducted using published primers for
TNF- TNF- THP-1 cells
cultured in 24-well plates were pretreated for 2 h at 37 °C
with either 100 µM TLCK; (Sigma), 20 µM H7
(Calbiochem), 10 µM H89 (Calbiochem), 2 µM
HA (Sigma), or 10 µM U73122 (Calbiochem), following which
they were incubated with 100 nM Tat. Separate samples were
analyzed for TNF- RESULTS To determine if Tat could stimulate TNF-
In brain, TNF- Although we used highly purified cultures of macrophages and
astrocytes, we could not exclude the possibility of small amounts of
other contaminating cell types in these cultures. Hence we also used a
human monocytoid (THP-1) and astrocytic (U373) cell line to determine
TNF-
All experiments were conducted with highly purified recombinant Tat
protein. Yet we considered the possibility that TNF- To determine if the induction of TNF- Previous studies had shown that Tat induces NF-
DISCUSSION We have demonstrated that the Tat protein of HIV-1 induces TNF- TNF- Tat-induced TNF- Consistent with previous studies demonstrating that TNF- Tat is formed from two exons. The first exon contributes to the first
72 amino acids and the second to another 14-22 amino acids. Here we
show that Tat derived from the first exon (Tat1-72) is sufficient to
induce TNF- In conclusion, the HIV-1 protein, Tat, is an important stimulus for
TNF- FOOTNOTES ACKNOWLEDGEMENTS We thank Mark Bernier and Carol Martin for
assistance with astrocyte cultures, Tanis Benidictson for preparing the
recombinant Tat protein, Terry Langelier for preparing macrophage
cultures, and Weimin Ni for assistance with ELISAs.
REFERENCES
Volume 272, Number 36,
Issue of September 5, 1997
pp. 22385-22388
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
Production
IMPLICATIONS FOR HIV-1-ASSOCIATED NEUROLOGICAL DISEASES*
,§,¶ and¶
Medical Microbiology and
Section of Neurology, ¶ Department of Medicine, University of
Manitoba, Winnipeg, Manitoba, Canada R3E 0W3
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
,
both of which occur in an environment of small numbers of infected
cells. We examined the possibility that HIV protein Tat, which is
released extracellularly from infected cells, may induce the production of TNF-. Tat induced TNF- mRNA and protein production
dose-dependently, primarily in macrophages but also in
astrocytic cells. The TNF- induction was
NF-
B-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF- release was also linked to phospholipase C
activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link
between HIV and macrophage/glial cell activation and suggest new
therapeutic approaches for HIV dementia.
(4-7). TNF- mRNA and protein levels are
increased in brains of individuals with HIV infection, and the severity
of dementia is closely correlated with TNF- levels (8, 9). Although
under certain conditions, TNF- may have neuroprotective properties
(10, 11), this molecule also has multiple damaging effects on cells in
the central nervous system. For example, TNF- may cause apoptosis in
human neuronal cultures (12) and damage myelin (13). TNF- mediated
signaling events such as ceramide formation, tyrosine kinase
activation, NF-B activation, calcium mobilization and release,
reactive oxygen species formation (14) have been associated with
neurotoxicity. Additionally, excess levels of TNF- inhibit glutamate
uptake by astrocytes (15). TNF- may cause immune dysregulation by inducing interleukin-6, interleukin-8, and colony-stimulating factors
(16) and by inducing the expression of adhesion molecules on
endothelial cells (17). TNF- expression, however, is not up-regulated in HIV-infected macrophages unless they are co-cultured with astrocytes, upon which high levels of TNF- are released, suggesting that an intermediary factor is required for TNF-
production (4).
B (20, 21) and neurotoxicity (22-25). Tat may act
directly on neurons to cause excitotoxicity (24, 26) and cell death by
apoptosis (27). Additionally, Tat may act on glial cells to cause the
release of neurotoxic substances (28). This study examines this later
possibility by determining the ability of Tat to induce the production
of TNF- in various cell types and determine the mechanisms involved during TNF- induction by Tat. Previous studies have shown that TNF- production is regulated by NF-B induction (29) and that Tat
can induce NF-B activation in glial cells (20). Furthermore, intracerebral injection of a peptide derived from Tat into rat brain
caused increased cytokine production, including TNF- (30). Thus, we
performed experiments to determine the extent to which Tat induces
TNF- production and identify mechanisms involved in TNF-
overexpression.
-mercaptoethanol. All cell types were supplemented with 100 µg of
streptomycin/ml and 0.25 µg of amphotericin/ml. The U373 cells and
astrocytes were cultured to approximately 95% confluence in 24-well
plates (
1 × 106 cells/ml). PBMC, macrophage, and
THP-1 cells were cultured at a density of 2.5 × 106,
2.0 × 105, and 1.5 × 106 cells/ml,
respectively.
and -actin as described previously (33). -Actin primers
served as internal controls in each reaction. PCR products were
resolved in a 1.5% agarose gel and transferred to a nylon membrane and
probed with [32P]ATP end-labeled oligonucleotide probes
to TNF- or -actin as described (34). TNF- and -actin
oligonucleotide probes were designed based on the products amplified
when using the above primers (TNF-, 5
-CAAGCTGAGGGGCAGCTCCAGTGG-3;
-actin, 5-GAGACCTTCAACACCCCAGCCATGT-3).
in tissue
culture supernatants was determined by a sandwich ELISA (35). Briefly,
microtiter plates were coated with 2 µg/ml purified monoclonal
antiserum to human TNF- (PharMingen). A biotin-labeled mouse
anti-human TNF- antiserum (0.5 µg/ml) directed against a different
epitope (PharMingen) identified TNF- in the supernatants. The assay
detected TNF- at concentrations as low as 5 pg/ml. Serial doubling
dilutions of human recombinant TNF- (1250 to 4.5 pg/ml) were used to
generate a standard curve. All samples were analyzed in triplicates and
expressed as mean ± S.D.
mRNA and protein. Each experiment was
conducted in triplicate and repeated at least three times. Cell
viability was monitored by trypan blue exclusion.
production, we
conducted initial experiments with macrophages, since previous studies have shown that macrophages are the major source of TNF- and observed that Tat could induce TNF- in the culture supernatants. TNF- induction was dose- and time-dependent (Fig.
1, A and B), with
significant increases seen at concentrations of 10 nM Tat (7.03 ± 1.84 ng/ml versus 0.46 ± 0.25/ng/ml;
p < 0.05). TNF- release occurred as early as 1 h after stimulation and peaked by 4 h (Fig. 1A).
Fig. 1.
Time and dose dependence of Tat-mediated
TNF- production in primary cells. Cells were treated with Tat
as described under "Experimental Procedures," and supernatant
TNF- levels were determined by ELISA. A and B,
blood-derived macrophages; C and D, fetal
astrocytes; E and F, THP-1 cells. For the time course experiments, blood-derived macrophages (A) and THP-1
cells (E) were stimulated with 100 nM Tat, while
fetal astrocytes (C) were stimulated with 1 µM
Tat. The dose profiles shown were analyzed following treatment with Tat
for 4 h for each cell type. Each value represents the mean ± S.D. of three experiments conducted in triplicate.
[View Larger Version of this Image (19K GIF file)]
is primarily produced by tissue macrophages similar
to that in blood (1, 8). To determine if Tat could release TNF- in
astrocytes, we used highly purified human fetal astrocyte cultures.
Although Tat could induce TNF- in these cells, the dose and time
profile was different than that in macrophages (Fig. 1, C
and D). Significant (p < 0.05) increases
were observed at only dosages of 1 µM Tat, and the peak
levels occurred within 1 h after which there was a progressive
decline in TNF- production (Fig. 1, C and
D).
induction in response to Tat. Both cell lines responded to Tat.
The effect of Tat (1 µM) on U373 cells (0.80 ± 0.07 ng of TNF-/ml/106 cells) was comparable with that of
fetal astrocytes (1.20 ± 0.11 ng of TNF-/ml/106
cells), while THP-1 cells responded to Tat 
the dosage
needed for the astrocyte cell lines (Fig. 1, C and E). Primary macrophages produced 6-fold more TNF-
(15.00 ± 1.05 ng/ml/106 cells) than the THP-1 cells
(2.03 ± 0.23 ng/ml/106 cells) with 100 nM
Tat (Fig. 1, B and F). The time course of TNF-
induction in both cell lines was similar (Fig. 1, A and E). With LPS (positive control), TNF- was induced in the
macrophages (18.20 ± 0.89 ng/ml/106 cells; Fig.
2) and THP-1 cells (9.27 ± 0.17 ng/ml/106 cells). In astrocytes and U373 cells, although
there was a small induction of mRNA for TNF- with LPS (Fig.
3), levels of TNF- in culture
supernatants was below the level of detection for the ELISA. Tat was
thus a more potent inducer of TNF- protein production as compared
with LPS.
Fig. 2.
Specificity of induction of TNF- by Tat in
macrophages. Blood-derived macrophages showed an induction of
TNF- in response to LPS (1.0 µg/ml), Tat (100 nM), and
when Tat (100 nM) was incubated in the presence of
preimmune rabbit sera (Prs + Tat). No response was seen to
Prs or Tat antiserum alone. The effect of Tat could be eliminated by
digestion with trypsin or by immunoabsorption with Tat antiserum
(Tatim) (see "Experimental Procedures"). Data represents
the mean ± S.D. of four experiments conducted in
triplicate.
[View Larger Version of this Image (8K GIF file)]
Fig. 3.
Induction of TNF- mRNA in monocytoid
and astrocytic cells. THP-1 or U373 cells were treated with Tat,
and TNF- mRNA levels were analyzed by RT-PCR followed by
Southern blot analysis and compared with that of -actin. In
A, numbers on top indicate h following
treatment with 100 nM Tat, which shows a
time-dependent increase in TNF- mRNA levels in THP-1
cells. B, TNF- mRNA induction in THP-1 cells was seen
with 10 nM Tat and increased dose-dependently. C, U373 cells: lane 1, mock (PBS)-treated;
lane 2, LPS (1 µg/ml)-treated; and lane 3, Tat
(100 nM) treatment shows a small induction of TNF-
mRNA.
[View Larger Version of this Image (47K GIF file)]
induction could
be due to a contaminant in the Tat preparation. We prepared a trypsin
digest of Tat and incubated it with macrophages, since they were most
sensitive to induction of TNF- by Tat. No response was noted in
these cells (Fig. 2). Cellular response to Tat was also eliminated by
immunoabsorption of Tat with Tat antisera, but not with preimmune
rabbit sera, confirming the specificity of Tat action (Fig. 2). Similar
results were also seen with THP-1 cells (data not shown).
by Tat occurred at the level
of transcription or translation, we measured TNF- mRNA from
THP-1 cells using semiquantitative RT-PCR. Tat induced TNF- mRNA
expression in a dose- and time-dependent manner similar to TNF- protein detection (Fig. 3, A and B). 10 nM Tat produced increases in TNF- mRNA as early as
1 h, peaking by 4 h and returning to base line by 12 h
(Fig. 3A). A small induction in of TNF- mRNA was also
seen in the U373 cells in response to 100 nM Tat (Fig.
3C).
B activation (20) and
that NF-B regulates TNF- production (29). Hence, we conducted
experiments to determine if TLCK, a specific blocker of NF-B
activation, could affect Tat-induced TNF- expression. Pretreatment
of THP-1 cells with TLCK caused complete block of TNF- mRNA
(Fig. 4A) and protein
production (Fig. 4C). Since IB is phosphorylated by
protein kinases, we used specific blockers for protein kinase C (H7),
protein kinase A (H89), and for tyrosine kinase (HA) to identify
signaling cascades that are Tat-mediated and activate NF-B. Both H89
and HA were able to block Tat-induced TNF- mRNA and protein
production while H7 had no effect (Fig. 4, B and
C). To determine the role of phospholipase C in this cascade, we pretreated THP-1 cells with U73122, which also blocked the
effect of Tat on TNF- (Fig. 4, B and C).
Treatment of the cells with Tat or any of the above pharmacological
agents did not effect cell viability (data not shown).
Fig. 4.
Role of NF-B, protein kinases, and
phospholipase C in Tat-induced TNF- induction. A and
B, Tat (100 nM)-mediated induction of TNF-
mRNA in THP-1 cells was determined by RT-PCR followed by Southern
blot analysis. A: lane 1, cells treated with Tat
(100 nM); lane 2, cells treated with TLCK (100 µM) alone; lane 3, TLCK (100 µM) + Tat (100 nM); lane 4, LPS (1 µg/ml).
Comparatively, a lesser amount of PCR product was loaded in lane
4 due to the strong TNF- signal. B, cells were
either mock (PBS)-treated (lane 1) or treated with U73122
(10 µM) alone (lane 2), U73122 (10 µM) + Tat (100 nM) (lane 3), H7
(20 µM) alone (lane 4), H7 (20 µM) + Tat (100 nM) (lane 5), HA (2 µM) alone (lane 6), HA (2 µM) + Tat (100 nM) (lane 7), H89 (10 µM)
alone (lane 8), H89 (10 µM) + Tat (100 nM) (lane 9), or Tat (100 nM) alone
(lane 10). C, a corresponding block in Tat (100 nM)-induced TNF- protein production was seen in tissue
culture supernatants with TLCK, H89, HA, and U73122 as determined by
ELISA. Each value represents the mean ± S.D. of three experiments
conducted in triplicate.
[View Larger Version of this Image (28K GIF file)]
expression in macrophages and astrocytes. Since TNF- up-regulates HIV expression in infected macrophages (36, 37) and glial cells (38),
and there is an increased expression of TNF- receptors on
macrophages and microglial cells in the brains of patients with HIV
infection (39), perhaps a positive feedback loop exists whereby only
small numbers of infected cells may be necessary to produce substantial
amounts of Tat and TNF-. Furthermore, since both Tat and TNF- are
implicated in neurotoxicity, the neurotoxic effects of Tat would be
amplified by its ability to induce TNF-.
mRNA levels are elevated in the brains of patients with HIV
infection and dementia (6, 8, 40). Viral transcripts are also increased
in patients with HIV dementia (40). These findings support our
observations that the expression of viral transcripts, such as Tat, and
cytokines, such as TNF-, are tightly linked and
interdependent.
production was noted in cells of monocytic lineage
and in astrocytes. The macrophages, however, responded to much lower
dosages of Tat and produced larger amounts of TNF-. Previous studies
using different stimuli have also shown that TNF- is predominantly
produced by cells of monocytic lineage (14, 41). Furthermore, brain
tissue from adults with AIDS shows that TNF- immunoreactivity is
primarily present in microglial cells and occasionally in astrocytes
(1, 9). However, since astrocytes are the most numerous cell type in
the brain and outnumber microglia by several logfold Tat-induced
TNF- production by astrocytes may be biologically significant. In
fact, astrocytes can induce HIV replication in macrophages, which is
dependent upon the production of TNF- by astrocytes (42). This may
particularly be important for the pathogenesis of HIV dementia in
children, since in vitro studies have shown that virtually
all human fetal astrocytes are capable of producing TNF- as opposed
to adult astrocytes where only a minority of cells could be induced to
express TNF- in response to agents such LPS and interferon 
(41).
Since HIV dementia occurs much more frequently in children than adults, differential TNF- induction by fetal and adult astrocytes may, in
part, account for these differences.
production
is regulated by NF-B (29), we observed that Tat-induced TNF-
production was similarly regulated. However, in contrast to previous
observations where macrophage TNF- production may be be regulated by
protein kinase C (43), we found that inhibition of protein kinase C had
no effect on Tat-induced TNF- mRNA or protein production.
Instead, Tat-induced TNF- production was protein kinase A- and
protein tyrosine kinase-dependent. Thus, the regulation of
TNF- gene induction by protein kinases is stimulation-specific. It
is likely that these protein kinases are directly or indirectly linked
to phospholipase C, since inhibition of phospholipase C also blocked
Tat-induced TNF- production. Although the cascade of events leading
to TNF- production by Tat needs to be further examined, it has been
suggested that Tat-mediated inhibition of manganese-dependent superoxide dismutase may also play a
role (44).
induction. We have previously shown that Tat1-72 is
poorly internalized (21) and that a number of physiological effects of
Tat1-72, such as neuronal excitation (25), increases in intracellular
calcium, and NF-B induction (19), are mediated by interactions of
Tat with the cell membrane. It is thus likely that Tat-induced TNF-
production is also a membrane-triggered event; however, further studies
are necessary to determine the mechanism of TNF- induction by
Tat.
production by macrophages and glial cells and that even
transient expression of Tat may have detrimental effects on the brain
of HIV-infected patients. Thus, therapeutic approaches using combined
antiretroviral and anti-TNF- therapy should be considered for the
treatment of HIV dementia.
§
Recipient of a Faculty of Medicine Fellowship, University of
Manitoba.
To whom correspondence should be addressed: Dept. of
Neurology, University of Kentucky, Kentucky Clinic, Room L-445,
Lexington, KY 40536-0284. Tel.: 606-323-1279; Fax: 606-323-5943.
1
The abbreviations used are: HIV, human
immunodeficiency virus; ELISA, enzyme-linked immunosorption assay; FBS,
fetal bovine serum; HA, herbimycin A; LPS, lipopolysaccharide; PBMC,
peripheral blood mononuclear cells; PBS, phosphate-buffered saline; RT,
reverse transcription; PCR, polymerase chain reaction; TLCK,
N
-p-tosyl-L-lysine
chloromethyl ketone; TNF-, tumor necrosis factor-.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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J. M. Weiss, A. Nath, E. O. Major, and J. W. Berman HIV-1 Tat Induces Monocyte Chemoattractant Protein-1-Mediated Monocyte Transmigration Across a Model of the Human Blood-Brain Barrier and Up-Regulates CCR5 Expression on Human Monocytes J. Immunol., September 1, 1999; 163(5): 2953 - 2959. [Abstract] [Full Text] [PDF]
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R. A. Boykins, R. Mahieux, U. T. Shankavaram, Y. S. Gho, S. F. Lee, I. K. Hewlett, L. M. Wahl, H. K. Kleinman, J. N. Brady, K. M. Yamada, et al. Cutting Edge: A Short Polypeptide Domain of HIV-1-Tat Protein Mediates Pathogenesis J. Immunol., July 1, 1999; 163(1): 15 - 20. [Abstract] [Full Text] [PDF]
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A. Nath, K. Conant, P. Chen, C. Scott, and E. O. Major Transient Exposure to HIV-1 Tat Protein Results in Cytokine Production in Macrophages and Astrocytes. A HIT AND RUN PHENOMENON J. Biol. Chem., June 11, 1999; 274(24): 17098 - 17102. [Abstract] [Full Text] [PDF]
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D. R. New, S. B. Maggirwar, L. G. Epstein, S. Dewhurst, and H. A. Gelbard HIV-1 Tat Induces Neuronal Death via Tumor Necrosis Factor-alpha and Activation of Non-N-methyl-D-aspartate Receptors by a NFkappa B-Independent Mechanism J. Biol. Chem., July 10, 1998; 273(28): 17852 - 17858. [Abstract] [Full Text] [PDF]
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A. Poggi, A. Rubartelli, and M. R. Zocchi Involvement of Dihydropyridine-sensitive Calcium Channels in Human Dendritic Cell Function. COMPETITION BY HIV-1 TAT J. Biol. Chem., March 27, 1998; 273(13): 7205 - 7209. [Abstract] [Full Text] [PDF]
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 K. Conant, A. Garzino-Demo, A. Nath, J. C. McArthur, W. Halliday, C. Power, R. C. Gallo, and E. O. Major Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia PNAS, March 17, 1998; 95(6): 3117 - 3121. [Abstract] [Full Text] [PDF]
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