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Journal of Virology, January 2001, p. 192-198, Vol. 75, No. 1
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.1.192-198.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Reciprocal Interactions between Human
T-Lymphotropic Virus Type 1 and Prostaglandins: Implications for
Viral Transmission
Masako
Moriuchi,1
Hiroyasu
Inoue,2 and
Hiroyuki
Moriuchi1,3,*
Division of Medical Virology, Department of
Molecular Microbiology and Immunology, Nagasaki University Graduate
School of Medical Sciences,1 and
Department of Pediatrics, Nagasaki University School of
Medicine,3 Nagasaki, and Department
of Pharmacology, National Cardiovascular Center Research Institute,
Osaka,2 Japan
Received 15 May 2000/Accepted 22 September 2000
 |
ABSTRACT |
Human T-lymphotropic virus type 1 (HTLV-1), the etiologic agent of
adult T-cell leukemia/lymphoma, is transmitted through breast milk and
seminal fluid, which are rich in prostaglandins (PGs). We demonstrate
that PGE2 upregulates the HTLV-1 long terminal repeat
promoter through the protein kinase A pathway, induces replication of
HTLV-1 in peripheral blood mononuclear cells (PBMC) derived from
asymptomatic carriers, and enhances transmission of HTLV-1 to cord
blood mononuclear cells (CBMC). Furthermore, HTLV-1 Tax transactivates
a promoter for cyclooxygenase 2, a PG synthetase, and induces
PGE2 expression in PBMC or CBMC. Thus, HTLV-1 interacts
with and benefits from PGs, constituents of its own vehicle for transmission.
| |
INTRODUCTION |
Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma and
is transmitted horizontally or vertically through blood, seminal fluid,
or breast milk (reviewed in references 13 and
37).
Prostaglandins (PGs) are synthesized and secreted by most human tissues
and cell types; however, they are especially abundant in seminal fluid
and breast milk (2, 7, 9, 10). PGs, particularly those of
the E series, are widely regarded as pleiotropic immunomodulatory
molecules, and regulation of their expression appears to be critical
for a number of immune responses (reviewed in references
26 and 29). There are two
isoforms of cyclooxygenase (COX) that catalyze the formation of PGs
from arachidonic acid. While COX-1 is a housekeeping gene
that is expressed constitutively, COX-2 is an
immediate-early response gene that is highly inducible by mitogenic and
inflammatory stimuli and is considered essential for the induction of
the aforementioned immune responses (reviewed in reference
32).
In this study we demonstrate that (i) PGE2 upregulates the
HTLV-1 long terminal repeat (LTR) promoter through the protein kinase A
(PKA) pathway, induces viral replication in peripheral blood
mononuclear cells (PBMC) derived from asymptomatic HTLV-1 carriers, and
enhances transmission of HTLV-1 to cord blood mononuclear cells (CBMC)
and that (ii) HTLV-1 Tax transactivates a COX-2 promoter and
induces PGE2 production in PBMC. These data suggest that
HTLV-1 interacts with and benefits from PGs that are abundant in
seminal fluid and breast milk, vehicles for virus transmission.
| |
MATERIALS AND METHODS |
Reagents.
PGE2, H7, HA-1004, mitomycin C (MMC),
3'-azido-3'-deoxythymidine (AZT), phorbol 12-myristate 13-acetate
(PMA), and ionomycin were purchased from Sigma (St. Louis, Mo.). MMC
treatment of cells was performed as described previously
(1).
Infectious HTLV-1 stock which was rendered devoid of cell culture
supernatants by directly pelleting virions was obtained from Advanced
Biotechnologies, Inc. (Columbia, Md.). Glutathione S-transferase (GST) and GST-Tax protein were propagated as
described previously (23).
Plasmids and transient-expression assays.
pU3R-luc, a
generous gift of K.-T. Jeang (National Institute of Allergy and
Infectious Diseases [NIAID], Bethesda, Md.), carries the luciferase
gene under the control of the HTLV-1 LTR. Plasmids pMT-2T (parent
plasmid), pMT-Tax (encoding HTLV-1 Tax), pMT-p65 (encoding a NF-
B
p65 subunit), and pMT-IB (encoding I-B
) were kindly provided
by U. Siebenlist (NIAID) (23). The human COX-2 promoter-luciferase reporter plasmids phPES(
1432/+59),
phPES(327/+59), phPES(220/+59), phPES(124/+59), phPES(52/+59),
phPES-KBM (with a mutation at the NF-B site), phPES-ILM (with a
mutation at the NF-IL6 site), phPES-CRM (with a mutation at the cyclic
AMP-responsive element [CRE]), phPES-KBM/ILM (with mutations at both
the NF-B and NF-IL6 sites), phPES-KBM/CRM (with mutations at both
the NF-B site and the CRE), phPES-ILM/CRM (with mutations at both
the NF-IL6 site and the CRE), and phPES-KBM/ILM/CRM (with mutations at
all three elements) were described previously (14, 15).
Transfection of the human Jurkat T leukemia cell line or PBMC and
luciferase assays for transient-expression assays were performed
as
described previously (
22). Briefly, 20 million Jurkat
cells
or 40 million PBMC were transfected by electroporation at 300
or
320 V, respectively, and 975 µF with a Gene Pulser II (Bio-Rad,
Hercules, Calif.). After electroporation, cells were cultured
in RPMI
1640 supplemented with 10% fetal bovine serum (FBS) at
37°C for
40 h. Luciferase activity was determined by using a luciferase
assay kit (Promega, Madison, Wis.) with a TD-20e luminometer
(Turner).
Measurement of PGE2.
The concentration of
PGE2 in the cell culture supernatants was determined in
triplicate by enzyme-linked immunosorbent assays (ELISA) according to
the manufacturer's instructions (R&D Systems, Minneapolis, Minn.).
Where indicated, cells were infected with cell-free HTLV-1 stock (1 µg of protein per 3 × 106 cells) or were treated
with GST or GST-Tax at a concentration of 100 ng/ml before cell-free
supernatants were collected for PGE2 measurement.
HTLV-1 infection.
For HTLV-1 infection studies, PBMC were
obtained from buffy coats of asymptomatic HTLV-1 carriers (Nagasaki
Red-Cross Center, Nagasaki, Japan) as described previously
(21). The cells were incubated in 24-well culture dishes
at a concentration of 3 × 106 per ml in RPMI 1640 supplemented with 10% FBS in the presence or absence of
PGE2 (100 nM).
For HTLV-1 transmission studies, cord blood samples were provided by
the Pre- and Post-Natal Care Unit, Nagasaki University
School of
Medicine Hospital, with consent by donors, and CBMC
were cocultured
with MMC-treated PBMC obtained from HTLV-1 carriers
in the presence or
absence of PGE
2 immediately after isolation.
Cell-free
culture supernatants were collected on day 7 for measurement
of HTLV-1
p19 antigen by ELISA (Cellular Products Inc., Buffalo,
N.Y.).
| |
RESULTS AND DISCUSSION |
PGE2 upregulates HTLV-1 LTR activity.
In order to
assess whether PGE2 could influence expression of HTLV-1,
we first performed transient-expression assays. HTLV-1 LTR activity was
upregulated by stimulation with PGE2 in a dose-dependent manner (Fig. 1A). Since PGE2
levels in seminal fluid and breast milk whey were reported to be 1 to
~70 µM (2, 7, 27) and ~30 nM (10),
respectively, and since an overproduction of PGE2 (up to
100 µM) is seen in a number of medical situations (e.g., allergy,
hyper-immunoglobulin E syndrome, Hodgkin's lymphoma, trauma, sepsis,
and transplantation) (29), the PGE2-mediated effect appears to be physiologically relevant. PGE2
induction of HTLV-1 LTR activity was markedly abolished by H7 (a
selective serine/threonine kinase inhibitor that can inhibit PKA, PKC,
and PKG) and HA-1004 (a PKA and PKG inhibitor) (Fig. 1B and C). Since PGE2 has been shown to elevate the level of intracellular
cyclic AMP, which activates PKA (27), it is reasonable to
assume that PKA activity is required for transcriptional activity of
HTLV-1.
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FIG. 1.
PGE2 upregulates HTLV-1 LTR activity. (A)
PGE2 upregulates HTLV-1 LTR activity in a dose-dependent
manner. A total of 40 million PBMC were transfected with 10 µg of
pU3R-luc and were left unstimulated or were stimulated with the
indicated amount of PGE2, and luciferase activity of the
transfected cell lysates was assayed 2 days posttransfection. Fold
induction is the luciferase activity relative to that obtained without
PGE2 treatment. Results are means ± standard errors
of the means from three independent experiments. (B and C) PKA activity
is involved in PGE2 induction of expression from the HTLV-1
LTR. A total of 40 million PBMC (B) or 20 million Jurkat cells (C) were
transfected with 10 µg of pU3R-luc, and luciferase activity of the
transfected cell lysates was assayed 2 days posttransfection. Where
indicated, cells were treated with PGE2 (100 nM) in the
presence or absence of H7 (1 µM) or HA-1004 (1 µM) for 8 h
before harvest. Fold induction is the luciferase activity relative to
that obtained in the absence of the reagents. Results are means ± standard errors of the means from six independent experiments.
|
|
PGE2 induces HTLV-1 replication.
In order to
determine whether PGE2 could actually induce replication of
HTLV-1, we incubated PBMC obtained from asymptomatic HTLV-1 carriers in
the presence or absence of PGE2. Stimulation with
PGE2 enhanced HTLV-1 infection four- to fivefold as
determined by HTLV-1 p19 antigen (Ag) levels (Table
1). Treatment with AZT (2 µM) resulted
in a markedly decreased expression of p19 Ag (Table 1). Since AZT has
no antiretroviral effect on PBMC already infected with HTLV-1
(18), profound suppression of p19 expression by AZT would
indicate that induction of HTLV-1 expression in the presence of
PGE2 required the expansion of HTLV-1 infection. Addition of PGE2 to the cell culture medium did not appear to
influence cell viability as determined by trypan blue exclusion (data
not shown). Thus, PGE2, a constituent of seminal fluid and
breast milk, appears to induce replication of HTLV-1.
We next investigated whether PGE
2 could accelerate
transmission of HTLV-1 to CBMC. Uninfected CBMC were cocultured with
MMC-treated
carriers' PBMC at a ratio of 10:1 in the presence or
absence of
PGE
2. It has been shown that MMC-treated cells
can no longer support
new cycles of retroviral infection
(
1). As shown in Table
2,
the p19 level in the coculture supernatants was increased by treatment
with PGE
2. PGE
2 treatment increased p19 Ag
levels in cultures
of MMC-treated carriers' PBMC; however, they were
much lower than
those in coculture of these cells with CBMC. These
results suggest
that expansion to susceptible CBMC is required for the
induction
of HTLV-1 replication. It has been reported that enterally
administered
milk leukocytes can invade suckling neonates and become
distributed
in their lymphoid tissues (
16,
36). Therefore,
although the
exact mechanisms and the target cells in the mucosa of
milk-borne
infection remain unknown, these results imply that
PGE
2 may accelerate
viral transmission from maternal
lymphocytes in breast milk to
neonatal lymphocytes.
HTLV-1 Tax transactivates the COX-2 promoter.
As
shown above, induction of PGE2 production is likely to
favor HTLV-1 infection and transmission; therefore, we next wanted to
investigate whether HTLV-1 infection could influence expression of
PGE2. The HTLV-1 Tax transactivator has been shown to
upregulate expression of a number of viral and cellular genes, which
usually contributes to viral replication or transformation (reviewed in references 6, 31, and 35). We
therefore tested whether Tax could upregulate promoter activity of
COX-2, a PG synthetase. As shown in Fig.
2A, coexpression of Tax alone upregulated
the COX-2 promoter-luciferase reporter activity in the
Jurkat human T-cell line. Tax alone was a relatively weak
transactivator for the COX-2 promoter in PBMC (Fig. 2B);
however, stimulation with PMA plus ionomycin in addition to Tax
synergistically upregulated the COX-2 promoter activity in
PBMC (Fig. 2B). Such synergy has been observed for other Tax-mediated
effects (11, 23). We have also demonstrated that
COX-2 promoter activity was upregulated in PBMC treated with
purified Tax protein (GST-Tax) (Fig. 2C).
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FIG. 2.
HTLV-1 Tax transactivates the COX-2 promoter.
Jurkat cells (A) or PBMC (B) were transfected with 10 or 40 µg
of phPES(1432/+59), respectively, along with 10 µg of pMT-2T or
pMT-Tax, respectively. Where indicated, PBMC were stimulated with PMA
(1 µM) plus ionomycin (1 µM) for 8 h. Fold induction is the
luciferase activity relative to that obtained with phPES(1432/+59)
plus pMT-2T in the absence of PMA plus ionomycin. Results are
means ± standard errors of the means from six independent
experiments. (C) PBMC were transfected with 40 µg of
phPES(1432/+59) and treated with GST or GST-Tax (100 ng/ml) for 2 days. Results are means ± standard errors of the means from three
independent experiments.
|
|
In order to confirm that HTLV-1 infection or Tax protein induces
PGE
2 production, PBMC were infected with HTLV-1 or exposed
to purified Tax protein, and PGE
2 levels in the cell
culture supernatants
were determined by ELISA. HTLV-1-infected cells
secrete soluble
activity that exerts a number of biological activities
on neighboring
cells in a paracrine manner, and Tax protein released
from infected
cells is attributed, at least in part, to the soluble
activity
(
4,
17,
19,
23). Experiment results listed in
Tables
3 and
4 clearly demonstrate that HTLV-1
infection or Tax protein
could induce PGE
2 production.
Both NF-B and NF-IL6 sites are required in Tax activation of the
COX-2 promoter.
HTLV-1 Tax protein is not able to
directly bind to DNA; instead, it interacts with certain cellular
transcription factors to exert its transregulatory functions (reviewed
in references 6, 31, and 35). The
COX-2 promoter sequence contains several cis-acting elements (reviewed in reference
38), some of which have been shown to be involved in
Tax-mediated transactivation in other promoter contexts. In order to
determine the cis-acting elements involved in Tax-mediated
transactivation of the COX-2 promoter, we tested a number of
COX-2 promoter constructs in transient-expression assays. As
shown in Fig. 3A,
5' truncation of the promoter sequence down to position 327 modestly reduced responsiveness to Tax
activation, while truncation down to 220 markedly reduced
responsiveness. To further delineate the Tax-responsive region in the
promoter sequence spanning 327 to +59 relative to the transcription
start site, site-directed mutations were introduced individually or in
combination. As shown in Fig. 3B, elements for NF-B (which is
located between 223 and 214) and for NF-IL6 (which is located between 132 and 124) are both involved in Tax-mediated
transactivation of the COX-2 promoter: mutation at either of
them alone modestly abrogated Tax induction of COX-2
promoter activity, while mutations at both elements markedly abrogated
Tax induction of COX-2 promoter activity. In contrast,
mutation at the CREB/ATF site (which is located between 59 and 53)
had little effect on it. Involvement of NF-B in Tax activation of
the COX-2 promoter was also investigated by overexpressing
I-B, a specific inhibitor for NF-B. As expected, while
cotransfection of the NF-B p65 expression vector with the COX-2 promoter upregulated the promoter activity, I-B
counteracted p65-mediated activation (Fig. 3C). Similarly,
overexpression of I-B markedly abrogated Tax-mediated activation
of the COX-2 promoter (Fig. 3C), suggesting that the NF-B
pathway is critical for its effect. Another NF-B site is located
between 1432 and 327 (H. Inoue and T. Tanabe, unpublished data) and
may explain the partial responsiveness of the region to Tax (Fig. 3A).
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FIG. 3.
Both the NF-B and NF-IL6 sites are involved in Tax
activation of the COX-2 promoter. (A) Jurkat cells were
transfected with 10 µg of the luciferase reporter plasmid along with
10 µg of pMT-2T or pMT-Tax. Results are means ± standard errors
of the means from four independent experiments. Fold induction by Tax
of the respective luciferase reporter is shown to the right of the
bars. (B) Jurkat cells were transfected with 10 µg of the luciferase
reporter plasmid along with 10 µg of pMT-2T or pMT-Tax. Results are
means ± standard errors of the means from six independent
experiments. Fold induction by Tax of the respective luciferase
reporter is shown to the right of the bars. (C) Jurkat cells were
transfected with 10 µg of phPES(1432/+59) and 10 µg of pMT-2T,
pMT-p65, or pMT-Tax along with pMT-2T or pMT-IB. Results are
means ± standard errors of the means from four independent
experiments.
|
|
In the present study we have demonstrated that HTLV-1, which is
transmitted vertically or horizontally through breast milk
or seminal
fluid, respectively, and PGs, which are abundant in
these body fluids,
benefit from each other. These results confirm
a recent study
demonstrating that PKA activity is required for
HTLV-1 LTR activity
(
34) and further extend the understanding
of reciprocal
interactions between HTLV-1 and PGs. PGE
2 enhances
HTLV-1
replication by upregulating the HTLV-1 LTR promoter, and
HTLV-1 Tax
transactivates a promoter for
COX-2, a PG synthetase,
leading to production of PGE
2. Therefore, it is likely that
such
mutual aid helps accelerate viral transmission through seminal
fluid or breast milk. This hypothesis will require experimental
evidence.
PGs and other eicosanoids have been shown to play a key role in the
regulation of both humoral and cell-mediated immunity,
generally
tipping the balance in favor of Th2- and Th3-type responses
by
modulating cytokine and immunoglobulin production as well as
T-cell
proliferation and activation (reviewed in references
24 and
26). It therefore is not
surprising if PGs influence the
pathogenesis of infection with a number
of pathogens. In fact,
recent studies suggested that PGE
2
can modify infection with human
immunodeficiency virus type 1, another
human retrovirus that is
also transmitted through breast milk or
seminal fluid (
5,
33).
Thus, constituents such as PGs in
these body fluids may variably
influence viral transmission. We are
currently investigating PGE
2 levels in asymptomatic HTLV-1
carriers as well as effects of other
constituents in these body fluids
on HTLV-1 infection. Preliminary
results have indicated that several
other constituents also benefit
HTLV-1 infection (M. Moriuchi and H. Moriuchi, unpublished
data).
Although HTLV-1 has oncogenic potential, the mode of oncogenesis by
HTLV-1 is poorly understood. It has been shown that HTLV-1-encoded
Tax
protein is necessary and sufficient for cell immortalization
(reviewed
in references
20 and
35). Several
studies showed
that Tax-transgenic mice develop several types of
malignancy,
including leukemia, mesenchymal tumors, and neurofibromas
(
3,
8,
12,
25). Tax is able to interact with a number of
cellular
factors involved in transcription and/or cell cycling and is
considered
to induce cell transformation through such interactions
(reviewed
in references
20 and
35). Since PGs have also been associated
with
carcinogenesis (reviewed in reference
30), Tax
activation
of
COX-2 through cellular transcription factors
(i.e., NF-
B/Rel
family proteins) may contribute to HTLV-1-induced
oncogenicity.
In fact, a recent study has demonstrated that a number of
HTLV-1-transformed
cell lines do, but most HTLV-1-uninfected cell lines
do not, express
COX-2 mRNA (N. Mori [Institute of Tropical
Medicine, Nagasaki
University, Nagasaki, Japan], personal
communication), implying
a critical role in HTLV-1-induced
oncogenicity.
In summary, our studies have identified PGs as another target for
HTLV-1 Tax, and reciprocal interactions between HTLV-1 and
PGs may have
implications for its transmission and
oncogenesis.
| |
ACKNOWLEDGMENTS |
We thank K.-T. Jeang and U. Siebenlist for reagents, Nagasaki
Red-Cross Center and Pre- and Post-Natal Care Unit (Nagasaki University
Hospital) for providing blood samples, and K. Iijima and M. Yokoyama
for assistance with the figures. We also thank T. Tanabe for critical
reading of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, Nagasaki University School of Medicine, 1-7-1 Sakamoto,
Nagasaki 852-8501, Japan. Phone: 81-95-849-7297. Fax: 81-95-849-7301. E-mail: hiromori{at}net.nagasaki-u.ac.jp.
| |
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Journal of Virology, January 2001, p. 192-198, Vol. 75, No. 1
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.1.192-198.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
