Previous Article | Next Article 
Infection and Immunity, October 1998, p. 4989-4993, Vol. 66, No. 10
Departments of
Neurology,1
Anesthesiology,2
Pathology,3 and
Medicine,4 Albert Einstein College
of Medicine, Bronx, New York 10461
Received 12 January 1998/Returned for modification 19 February
1998/Accepted 6 July 1998
Cytokines play a significant role in the regulation of
Toxoplasma gondii in the central nervous system.
Cytokine-activated microglia are important host defense cells in
central nervous system infections. Recent evidence indicates that
astrocytes can also be activated by cytokines to inhibit intracellular
pathogens. In this study, we examined the effect of gamma interferon
(IFN- Toxoplasma gondii is an
important pathogen in the central nervous system and causes a severe
encephalitis in patients with AIDS. Cytokines play an important role in
the regulation of T. gondii replication in the central
nervous system (17). Gamma interferon (IFN- Recent evidence indicates that cytokines can also activate astrocytes
to inhibit growth of T. gondii (6, 8, 25, 27). For example, IFN- For this reason, we have chosen to study the effects of cytokines on
growth of T. gondii in a primary astrocyte culture. In this
study, we evaluated the effects of IFN- Primary astrocyte culture.
Murine astrocytes from
C57BL/6 × SV129 mice or syngeneic mice, deficient in iNOS
(iNOS Culture of T. gondii.
Tachyzoites from T. gondii ME49 were obtained by in vitro culture in Vero cells.
Parasites were harvested after 4 to 5 days in culture, resuspended in
minimal essential medium supplemented with 10% fetal bovine serum, and
used for infection of murine astrocyte cultures.
Chemicals and cytokines.
Murine recombinant IFN- Cytokine treatments.
Murine astrocytes were stimulated with
IFN- Determination of Toxoplasma growth.
Cultures
were infected with 105 T. gondii tachyzoites per
well (a 5:1 tachyzoite/host cell ratio) for 2 h. The monolayer was then extensively washed to remove extracellular tachyzoites and [3H]uracil (2.5 µCi per well) was added. T. gondii growth was determined 48 h later by the
[3H]uracil incorporation method described below. Before
cell harvesting, the appearance of the culture was checked to verify
that T. gondii-induced cell lysis had not begun. The
monolayer was washed three times with phosphate-buffered saline to
remove any nonincorporated [3H]uracil. The astrocyte
monolayer was then lysed by incubation in 0.1% sodium dodecyl sulfate
for 15 min at room temperature. Nucleic acids were precipitated by the
addition of 3 M trichloroacetic acid. The contents of the wells were
deposited on Whatman glass filters and washed extensively with 0.1 M
trichloroacetic acid, and then radioactivity was determined with a
liquid scintillation counter (21). For each experiment,
controls included murine astrocytes cultured in the absence of T. gondii. The radioactivity of these samples was always near
background levels, thus confirming that [3H]uracil
incorporation was specific to the parasite.
Measurement of nitric oxide.
Supernatants from astrocyte
cultures were collected after 72 h of incubation in cytokines, and
nitrite was assayed with the Griess reagent kit (Molecular Probes).
Briefly, a 150-µl aliquot of culture supernatant was mixed with
50 µl of the Griess reagent [0.05%
N-(1-naphthyl)ethylenediamine
dihydrochloride-0.5% sulfanilic acid in phosphoric acid] and diluted
with 1.3 ml of water, and absorbance was measured at 548 nm in a
spectrophotometer. The amount of nitrite in the sample was calculated
from a sodium nitrite standard curve.
Effect of NMMA or tryptophan on cytokine inhibition.
Murine
astrocytes were cultured as described above except that in some
experiments, either NMMA (final concentration of 400 µM) or
tryptophan (final concentration of 100 µg/ml) was added to the
culture at the time of cytokine addition. Tryptophan uptake by
astrocytes was measured by monitoring [3H]tryptophan
uptake as described by Pfefferkorn (28). IDO activity was
measured photometrically at 490 nm, by using the Ehrlich reagent to
monitor the degradation of tryptophan to kynurenine as described by
Däubener et al. (7).
Statistics.
Within each experiment, all conditions were
repeated in triplicate, and each experiment was replicated two to three
times. Data were analyzed by nonparametric (Wilcoxon signed-rank test) and/or parametric (Student t test and analysis of variance)
methods, using Sigma Stat version 1.0 (Jandel Scientific, San Rafael,
Calif.).
Effect of IFN-
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Effect of Cytokines on Growth of Toxoplasma
gondii in Murine Astrocytes
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
), tumor necrosis factor alpha (TNF-
), interleukin-6 (IL-6),
and IL-1 on the growth of T. gondii in a primary murine
astrocyte culture. Pretreatment of astrocytes with IFN- resulted in
65% inhibition of T. gondii growth. Neither TNF-, IL-1,
nor IL-6 alone had any effect on T. gondii growth. IFN-
in combination with either TNF-, IL-1, or IL-6 caused a 75 to 80%
inhibition of growth. While nitric oxide was produced by astrocytes
treated with these cytokines, inhibition of T. gondii
growth was not reversed by the addition of the nitric oxide synthase
inhibitor NG-monomethyl-L-arginine.
Furthermore, IFN- in combination with IL-1, IL-6, or TNF- also
induced inhibition in astrocytes derived from syngeneic mice deficient
in the enzyme inducible nitric oxide synthase. This finding suggests
that the mechanism of cytokine inhibition is not nitric oxide mediated.
Similarly, the addition of tryptophan had no effect on inhibition,
indicating that the mechanism was not mediated via induction of the
enzyme indoleamine 2,3-dioxygenase. The mechanism of inhibition remains
to be elucidated. Results from this study demonstrate that
cytokine-activated astrocytes are capable of significantly inhibiting
the growth of T. gondii. These data indicate that
astrocytes may be important host defense cells in controlling
toxoplasmosis in the brain.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
) has been
shown to prevent reactivation of Toxoplasma encephalitis in
mice (30). Tumor necrosis factor alpha (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6) are up-regulated in the
brains of mice with chronic toxoplasmosis (9, 15, 16).
Studies indicate that IFN-, TNF-, IL-1, and IL-6 may control the
growth of T. gondii in the brain via activation of microglia
(4, 5). Studies of mice indicate that cytokines induce
anti-Toxoplasma activity in microglia via a nitric oxide (NO)-mediated mechanism (10).
has been shown to inhibit growth of T. gondii in the glioblastoma cell line 86HG39 (6).
Inhibition was shown to be via induction of indoleamine 2,3-dioxygenase
(IDO), resulting in the degradation of intracellular tryptophan
(8). Pelloux et al. found that in the astrocytoma cell line
GHE, TNF- inhibited, IL-1 stimulated, and IFN- and IL-6 had no
effect on growth of T. gondii (25). Finally, in
primary human astrocytes, IFN- and IL-1 in combination have been
shown to inhibit growth of T. gondii via the production of
NO (27). Interpretation of these results is difficult due to
variability found in astrocyte cell lines and differences between tumor
cells and primary astrocytes.
, TNF-, IL-1, and IL-6 on
the replication of T. gondii ME49 in a primary murine astrocyte culture. The effects of these cytokines individually, and the
effects of IFN- in combination with IL-1, TNF-, and IL-6, on the
growth of T. gondii were examined. The ability of each of
these cytokines and cytokine combinations to induce nitric oxide
production was assessed by using the Griess reagent. A nitric oxide-mediated mechanism of cytokine inhibition of T. gondii
growth was addressed by using
NG-monomethyl-L-arginine (NMMA), a
nitric oxide inhibitor, and by using astrocytes derived from syngeneic
mice deficient in the enzyme inducible nitric oxide synthase (iNOS).
The IDO mechanism of inhibition was investigated via the addition of
exogenous tryptophan. The aim of this study was to clarify the effect
of cytokines on T. gondii replication in astrocytes and
increase our understanding of the role of astrocytes in the host
defense against T. gondii in the central nervous system.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
/; gift of C. Nathan) (22), were
cultivated from the brains of neonatal (less than 24 h old) mice.
Murine pups were sacrificed, the brain was removed from the cranium,
the forebrain was dissected and the meninges were removed. The tissue
was minced and incubated in 0.25% trypsin for 5 min at 37°C. After 5 min, the trypsin was inactivated with a solution containing DNase and
soybean trypsinase inhibitors, and the tissue was further disrupted by
trituration in a 20-ml pipette. The dissociated cells were filtered
through a 74-µm-pore-size Nitex mesh, centrifuged at 200 × g, suspended in growth medium at a concentration of
106 cells/ml, and plated onto
poly-L-lysine-coated dishes. Astrocytes were maintained in
endotoxin-free minimal essential medium (BRL-GIBCO, Gaithersburg, Md.)
supplemented with 20% fetal bovine serum (BRL-GIBCO), 5% glucose, and
100 U of penicillin and streptomycin (BRL-GIBCO) per ml. The growth
medium was changed every 3 days. After 7 days in vitro, a confluent
layer of 1 × 104 to 2 × 104
cells/cm2 of astrocytes is reached. By this method, cells
were found to be >95% astrocytes, as judged by positive staining for
glial fibrillary acidic protein. Cultures contained <5% microglia, as
identified by staining with the lectin BS1-B4 (catalog no. L-2895;
Sigma, St. Louis, Mo.). Astrocytes were dissociated in trypsin-EDTA, replated onto poly-L-lysine-coated coverslips or 24-well
plates at 104 cells/cm, and cultured for 7 to 10 days after
replating. These astrocytes were then infected with T. gondii ME49 as described below.
,
IL-1
, TNF-, and IL-6 were purchased from Genzyme (Cambridge,
Mass.). NMMA and L-tryptophan were obtained from Sigma.
[3H]uracil and [3H]tryptophan were
purchased from Amersham Pharmacia Biotech (Arlington Heights, Ill.).
The Griess reagent kit (catalog no. G-7921) was obtained from Molecular
Probes (Eugene, Oreg.).
, TNF-, IL-1 (each at 100 U/ml), or IL-6 (1 ng/ml), alone
or in combination, for 72 h prior to infection, and supernatants
were removed for determination of nitric oxide production. Cultures
were then infected with T. gondii and incubated for 48 h without cytokines, and growth was determined by the
[3H]uracil method described below. The percentage of
infected astrocytes for each condition was determined by counting the
number of infected cells per 500 cells under both phase and
immunofluorescence microscopy. Testing for each condition was performed
in triplicate. Immunofluorescence microscopy was performed with a 1:50
dilution of a commercial polyclonal rabbit anti-Toxoplasma
antibody (DAKO, Carpenteria, Calif.) followed by detection with
anti-rabbit fluorescein immunoglobulin G (Boehringer Mannheim,
Indianapolis, Ind.) as previously described (13). All
cultures were incubated in endotoxin-free medium, and no endotoxin
contamination was detected in any of the experimental cultures.
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
, TNF-, IL-1, and IL-6 on growth of T. gondii in murine astrocytes.
Astrocytes were pretreated with
cytokines and then infected with T. gondii, and growth was
measured 48 h after infection. The effect of treating astrocytes
with IFN-, TNF-, IL-1, and IL-6 alone and in combination is
presented in Fig. 1. IFN- inhibited the growth of T. gondii by approximately 65%
(P < 0.05), but there was no effect from IL-6,
TNF-, or IL-1 alone. IFN- in combination with either IL-6, IL-1,
or TNF- inhibited the growth of T. gondii in murine
astrocytes by approximately 75 to 80% (P < 0.05), a level 10 to 15% greater than that observed after treatment with IFN- alone (P < 0.05). The addition of IL-6 did not
reverse the inhibition of growth induced by either IFN--IL-1 or
IFN--TNF- in astrocytes. No inhibition of T. gondii
growth was seen with either IFN- alone or any of the IFN-
cytokine combinations when cytokines were added at the time of
infection or 24 h prior to infection (data not shown).
View larger version (22K):
[in a new window]
FIG. 1.
Effect of cytokines on growth of T. gondii in
mouse astrocytes. Cells were incubated with the cytokines IFN- (100 U/ml), IL1 (1 ng/ml), IL-6 (100 U/ml), and TNF- (100 U/ml) for
72 h before infection. Control cultures were incubated in medium
alone. [3H]uracil (2.5 µCi/ml) was added 2 h after
infection, and cells were harvested 48 h later. Results are
averages of three separate experiments. Bars indicate ± standard
error of the mean. *, significance at the P < 0.05 level versus control as calculated by Student's t test.
(Insert) Percentages of cells (mean ± standard deviation)
infected with T. gondii ME49 as determined by microscopy
(multiplicity of infection, 5:1). The difference between each cytokine
treatment and the control was significant at P < 0.05;
there was no significant difference between any of the various cytokine
treatments.
alone and in combination with each of
TNF-, IL-1, and IL-6 were also assessed microscopically. The level
of infection of cultures treated with cytokines was found to be <5%,
compared to 30 to 35% in the controls (Fig. 1, inset), which
correlated with the results of the uracil uptake assay. The percent
infected cells approximately doubled when IL-6 was added to other
cytokines (i.e., 1.2% infected with IFN- and 2.8% infected with
IFN--IL-6). While not statistically significant, this finding
raises the possibility that in astrocytes, as found for macrophages
(2), IL-6 may reverse part of the activation due to other
cytokines.
NO production in cytokine-treated astrocytes.
NO production
after treatment with each of the cytokine combinations is presented in
Table 1. NO levels in the controls (i.e., no cytokines added) were between 2 and 3 µM, and no increase in NO
was seen with IFN-, TNF-, IL-1, or IL-6 treatment alone. All
cytokine combinations resulted in a statistically significant elevation
in NO above the control level (P < 0.05):
IFN--IL-1, 9.9 µM; IFN--TNF-, 15.2 µM; and
IFN--IL-6, 5 µM. The addition of IL-6 to IFN--IL-1 decreased
the NO levels induced by IFN--IL-1 slightly, while the addition of
IL-6 to IFN--TNF- had no effect on NO production.
|
Effect of NMMA on cytokine inhibition of T. gondii
growth in murine astrocytes.
Addition of NMMA decreased nitrite
levels in all cytokine combinations to background levels (<2 µM) in
all cultures (Table 1). The presence or absence of NMMA during the 72-h
pretreatment with cytokines prior to infection of astrocytes with
T. gondii did not affect the cytokine-mediated inhibition of
T. gondii growth due to IFN--IL-1, IFN--IL-6,
IFN--IL-1-IL-6, IFN--TNF-, or IFN--TNF--IL-6 (Table
2) or to the individual cytokines (data not shown).
|
Effect of cytokines on growth of T. gondii in
iNOS/ murine astrocytes.
Treatment of
iNOS/ astrocytes with IFN--IL-1, IFN--IL-6,
IFN--IL-1 plus IL-6, IFN--TNF-, or IFN--TNF- plus
IL-6 inhibited the growth of T. gondii significantly (75 to
80%) (Table 3), as was seen with
syngeneic control murine astrocytes. In addition, as found for control
astrocytes, the addition of IL-6 had little or no effect on the degree
of inhibition caused by either IFN--IL-1 or IFN--TNF-. As
expected, no nitric oxide was detected in the supernatants from the
iNOS/ astrocytes after treatment with any of the
cytokine combinations (Table 3).
|
Effect of tryptophan on cytokine inhibition of T. gondii growth.
Tryptophan (100 µg/ml) added to cultures
stimulated with cytokines did not reverse inhibition of T. gondii growth caused by any of the cytokine treatments in
normal or in iNOS/ astrocytes (Table
4). Tryptophan uptake by astrocytes was
verified by [3H]tryptophan incorporation (28).
No IDO activity was detected in astrocytes with or without cytokine
stimulation.
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
The cytokines IFN-, TNF-, IL-1, and IL-6 are known to be
important in controlling the replication of T. gondii
in the brain. The importance of cytokine activation of microglia
in regulating T. gondii infection in the brain is well
established, but the role of astrocytes is less well understood.
Variable effects on the growth of T. gondii have been
demonstrated in different astrocyte tumor lines with IFN-, TNF-,
IL-1, and/or IL-6 treatment. In the glioblastoma cell line 86HG39,
IFN- alone has been shown to inhibit the growth of T. gondii, while in the glioblastoma cell line 87HG31, the
combination of TNF- and IFN- was required to inhibit growth
(6, 8); in GHE astrocytoma cells, TNF- but not IFN-
inhibited the growth of T. gondii (25).
Additionally, in astrocytoma cells, IL-1 was found to stimulate growth
and IL-6 had no effect on T. gondii growth (25).
In the present study using primary murine astrocytes, we have
demonstrated that pretreatment with IFN- alone or in combination with IL-1, IL-6, or TNF- but not IL-1, IL-6, or TNF- alone
significantly inhibited the growth of T. gondii in these
cells. This result is consistent with findings for glioblastoma cell
line 86HG39 (6) but in contrast to those for astrocytoma
cell line GHE (25). The absence of IFN--induced
inhibition in GHE astrocytoma cells may be due to the fact that in this
study, cells were pretreated with IFN- for only 24 h. Peterson
et al. (26) found that pretreatment with IFN- for 24 h did not activate murine astrocytes to inhibit T. gondii,
which is consistent with our observations. We found that murine
astrocytes needed to be pretreated with IFN- for 48 to 72 h to
induce inhibition. Similarly, Däubener et al. (6, 8)
found optimal inhibition with IFN- when glioblastoma cells were
pretreated for 72 h. Treatment of astrocytes with cytokines after
infection did not induce inhibition. Thus, priming of astrocytes by
IFN- is required for anti-Toxoplasma activity. This
phenomenon has also been reported for monocytes (3).
IFN- in combination with either IL-1, TNF-, or IL-6 inhibited
T. gondii growth in murine astrocytes. The effect of adding either IL-1, IL-6, or TNF- to IFN- significantly (by 15 to 20%) increased inhibition of growth induced by IFN- alone. Similarly, in
microglia, IFN- activation is enhanced by TNF-, IL-1, or IL-6
(4, 5). In macrophages, IL-6 has been reported to reverse the inhibition caused by IFN--IL-1 (2). In our study,
IL-6 did not reverse the inhibition caused by either IFN--IL-1 or IFN--TNF- in murine astrocytes. The effect of IL-6 is of
interest due to the implication that IL-6 plays an important role in
the immunopathogenesis of Toxoplasma encephalitis
(31).
IFN- in combination with IL-1 and other cytokines has been shown to
stimulate nitric oxide production via the enzyme iNOS in both human and
murine astrocytes (14, 19). Treatment of primary murine
astrocytes with IFN- in combination with other cytokines also
resulted in the production of nitric oxide. However, inhibition of
T. gondii growth was found to be nitric oxide independent, as demonstrated by the inability of NMMA to reverse the inhibition and
the ability of cytokines to inhibit T. gondii growth in
iNOS/ astrocytes.
IFN- has been shown to inhibit Toxoplasma growth via
induction of the enzyme IDO, which results in the degradation of
tryptophan in human fibroblasts, glioblastoma cells, retinal epithelial
cells, and macrophages (8, 12, 23, 24, 29). Additionally, the IDO pathway has been shown to be activated by IFN- and TNF- in some glioblastoma cells and native human astrocytes (7). In our study, the addition of tryptophan did not reverse the inhibition caused by the IFN- alone or IFN- in combination with either TNF-, IL-1, or IL-6, and no increase in IDO activity could be detected in astrocytes following cytokine treatment. These data suggest
that in murine astrocytes, cytokines inhibit T. gondii via
an IDO-independent pathway.
IFN--induced inhibition of T. gondii in endothelial cells
has been shown to be mediated by an IDO-independent mechanism and was
also demonstrated not to be mediated via nitric oxide or reactive oxygen intermediates (32). The presence of some other
mechanism(s) induced by cytokines is not surprising given the many
diverse effects that cytokines have on astrocyte functions (1,
20). For example, IL-1 induces a reactive astrocyte phenotype
characterized by the expression of TNF-, IL-6, and
colony-stimulating factor in astrocytes (20). IFN- also
induces many changes in cell physiology, including metabolic and
cytoskeletal changes. The cytokine-induced inhibition of T. gondii in astrocytes may be due to some of these generalized
effects on host cell function. It is possible that iron starvation
(11) or other reactive oxygen intermediates can be induced
by IFN- alone or in combination with other cytokines and that these
mechanisms, which are the focus of our current investigations, are
responsible for the cytokine-mediated inhibition of T. gondii growth in murine astrocytes. Whatever the mechanism(s)
involved, this study clearly demonstrates that cytokine-activated
astrocytes induce significant anti-Toxoplasma activity and
that IFN- is the primary cytokine mediating this inhibition.
The ability of cytokines to activate astrocytes to inhibit replication
of T. gondii may also be involved in the mechanism of
reactivated Toxoplasma infections in AIDS. For instance,
evidence suggests that in patients with AIDS, a shift from a Th1 to a
Th2 cytokine profile occurs in the brain (18). The presence
of the Th1 cytokines IFN-, TNF-, and IL-1 in the brain would
presumably activate astrocytes to exert anti-Toxoplasma
activity. Concomitantly, a shift to a Th2 cytokine profile, which is
accompanied by a decrease in IFN- and subsequent decreases in
TNF- and IL-1, might then promote growth of T. gondii in astrocytes. The effect of Th2 cytokines on T. gondii in astrocytes is not known, but data from our previous study (13) showed that astrocytes, when unstimulated by
IFN- or other cytokines, serve as excellent host cells for T. gondii, supporting extensive replication resulting in the lysis
and continual reinfection of astrocytes. This finding, in conjunction
with the Th1/Th2 shift hypothesis, suggests that astrocytes may play a pivotal role in the pathophysiology of Toxoplasma
encephalitis in the brains of patients with AIDS.
In conclusion, we found in murine astrocytes, IFN- alone or in
combination with IL-1, TNF-, or IL-6 significantly inhibited growth
of T. gondii. Although IFN--IL-1 and IFN--TNF-
induced NO production, inhibition was not found to be via an
NO-mediated mechanism. Cytokine-mediated inhibition was also not due to
induction of IDO. The NO/IDO-independent pathway responsible for
inhibition of T. gondii growth is currently under
investigation in our laboratory. Given that IFN- has been shown to
be the main cytokine controlling growth of T. gondii in the
brain and that TNF-, IL-1, and IL-6 are up-regulated in the brains
of mice with chronic toxoplasmosis, results from the present
study indicate astrocytes are most likely an important effector cell in
limiting T. gondii replication in the brain.
| |
ACKNOWLEDGMENTS |
|---|
Sandra K. Halonen is an Aaron Diamond Foundation Fellow. This work was supported in part by a grant from The Aaron Diamond Foundation and in part by PHS grant AI 39454.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Dept. of Pathology, Rm. F-504, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2142. Fax: (718) 430-8543. E-mail: lmweiss{at}aecom.yu.edu.
Editor: J. M. Mansfield
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
| 1. | Aloisi, F., G. Borsellino, A. Caré, U. Testa, P. Gallo, G. Russo, C. Peschle, and G. Levi. 1995. Cytokine regulation of astrocyte function: in vitro studies using cells from the human brain. Int. J. Dev. Neurosci. 13:265-274[Medline]. |
| 2. |
Beaman, M. H.,
C. A. Hunter, and J. S. Remington.
1994.
Enhancement of intracellular replication of Toxoplasma gondii by IL-6. Interactions with IFN and TNF.
J. Immunol.
153:4583-4587[Abstract].
|
| 3. | Channon, J. Y., and L. H. Kasper. 1996. Toxoplasma gondii-induced immune suppression by human peripheral blood monocytes: role of gamma interferon. Infect. Immun. 64:1181-1189[Abstract]. |
| 4. | Chao, C. C., S. Hu, G. Gekker, W. J. Novick, Jr., J. S. Remington, and P. K. Peterson. 1993. Effects of cytokines on multiplication of Toxoplasma gondii in microglial cells. J. Immunol. 150:3404-3410[Abstract]. |
| 5. | Chao, C. C., G. Gekker, S. Hu, and P. K. Peterson. 1994. Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J. Immunol. 152:1246-1252[Abstract]. |
| 6. |
Däubener, W.,
K. Pilz,
S. S. Zennati,
T. Bilzer,
H. G. Fischer, and U. Hadding.
1993.
Induction of toxoplasmostasis in a human glioblastoma by interferon .
J. Neuroimmunol.
43:31-38[Medline].
|
| 7. |
Däubener, W.,
N. Wanagat,
K. Pilz,
S. Seghrouchni,
H. G. Fischer, and U. Hadding.
1994.
A new simple, bioassay for human IFN-.
J. Immunol. Methods
168:39-47[Medline].
|
| 8. |
Däubener, W. C.,
L. Remscheid,
S. Nockemann,
K. Pilz,
S. Seghrouchni,
C. Mackenzie, and U. Hadding.
1996.
Anti-parasitic effector mechanisms in human brain tumor cells: role of interferon and tumor necrosis factor .
Eur. J. Immunol.
26:487-492[Medline].
|
| 9. | Deckert-Schlüter, M., S. Albrecht, H. Hof, O. D. Wiestler, and D. Schlüter. 1995. Dynamics of the intracerebral and splenic cytokine mRNA production in Toxoplasma gondii-resistant and -susceptible congenital strains of mice. Immunology 85:408-418[Medline]. |
| 10. |
Gazzinelli, R. T.,
I. Eltoum,
T. A. Wynn, and A. Sher.
1993.
Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF and correlates with the down regulated expression of inducible nitric oxide synthase and other markers of macrophage activation.
J. Immunol.
151:3672-3681[Abstract].
|
| 11. |
Gebran, S. J.,
Y. Yamamoto,
C. Newton,
T. W. Klein, and H. Friedman.
1994.
Inhibition of Legionella pneumophila growth by gamma interferon in permissive A/J mouse macrophages: role of reactive oxygen species, nitric oxide, tryptophan and iron(III).
Infect. Immun.
62:3197-3205 |
| 12. |
Gupta, S. L.,
J. M. Carlin,
P. Pyati,
W. Dai,
E. R. Pfefferkorn, and M. J. Murphy, Jr.
1994.
Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts.
Infect. Immun.
62:2277-2284 |
| 13. | Halonen, S. K., W. D. Lyman, and F. C. Chiu. 1996. Growth and development of Toxoplasma gondii in humans neurons and astrocytes. J. Neuropathol. Exp. Neurol. 55:1150-1156[Medline]. |
| 14. |
Hewett, S. J.,
J. A. Corbett,
M. L. McDaniel, and D. W. Choi.
1993.
Interferon- and interleukin-1 induce nitric oxide formation from primary mouse astrocytes.
Neurosci. Lett.
164:229-232[Medline].
|
| 15. | Hunter, C. A., C. W. Roberts, M. Murray, and J. Alexander. 1992. Kinetics of cytokine mRNA production in the brains of mice with progressive toxoplasmic encephalitis. Eur. J. Immunol. 22:2317-2322[Medline]. |
| 16. | Hunter, C. A., M. J. Litton, J. S. Remington, and J. S. Abrams. 1994. Immunocytochemical detection of cytokines in the lymph nodes and brains of mice resistant or susceptible to Toxoplasmic encephalitis. J. Infect. Dis. 170:939-945[Medline]. |
| 17. | Hunter, C. A., and J. S. Remington. 1994. Immunopathogenesis of toxoplasmic encephalitis. J. Infect. Dis. 170:1057-1067[Medline]. |
| 18. | Klein, S. A., J. M. Dobmeyer, T. S. Dobmeyer, M. Pape, O. G. Ottmann, E. B. Helm, D. Hoelzer, and R. Rossol. 1997. Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry. AIDS 11:1111-1118[Medline]. |
| 19. | Lee, S. C., D. W. Dickson, W. Liu, and C. F. Brosnan. 1993. Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma. J. Neuroimmunol. 46:19-24[Medline]. |
| 20. | Lee, S. C., D. W. Dickson, and C. F. Brosnan. 1995. Interleukin-1, nitric oxide and reactive astrocytes. Brain Behav. Immun. 9:345-354[Medline]. |
| 21. |
Mack, D. G., and R. McLeod.
1984.
New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A.
Antimicrob. Agents Chemother.
26:26-30 |
| 22. | MacMicking, J. D., C. Nathan, G. Hom, N. Chartrain, D. S. Fletcher, M. Trumbauer, K. Stevens, Q. W. Xie, K. Sokol, N. Hutchison, H. Chen, and J. S. Mudgett. 1995. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641-650[Medline]. |
| 23. |
Murray, H. W.,
A. Szuro-Sudol,
D. Wellner,
M. J. Oca,
A. M. Granger,
D. M. Libby,
C. D. Rothermel, and B. Y. Rubin.
1989.
Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages.
Infect. Immun.
57:845 |
| 24. | Nagineni, C. N., K. Pardhasaradhi, M. C. Martins, B. Detrick, and J. J. Hooks. 1996. Mechanisms of interferon-induced inhibition of Toxoplasma gondii replication in human retinal pigment epithelial cells. Infect. Immun. 64:4188-4196[Abstract]. |
| 25. | Pelloux, H., G. Pernod, B. Polack, E. Coursange, J. Richard, J. M. Verna, and P. Ambroise-Thomas. 1996. Influence of cytokines on Toxoplasma gondii growth in human astrocytoma-derived cells. Parasitol. Res. 82:598-603[Medline]. |
| 26. | Peterson, P. K., G. Gekker, S. Hu, and C. C. Chao. 1993. Intracellular survival and multiplication of Toxoplasma gondii in astrocytes. J. Infect. Dis. 168:1472-1478[Medline]. |
| 27. | Peterson, P. K., G. Gekker, S. Hu, and C. C. Chao. 1995. Human astrocytes inhibit intracellular multiplication of Toxoplasma by a nitric oxide-mediated mechanism. J. Infect. Dis. 171:516-518[Medline]. |
| 28. |
Pfefferkorn, E. R.
1984.
Interferon blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan.
Proc. Natl. Acad. Sci. USA
81:908-912 |
| 29. |
Pfefferkorn, E. R.,
M. Eckel, and S. Rebhun.
1986.
Interferon- suppresses the growth of Toxoplasma gondii in human fibroblasts through starvation for tryptophan.
Mol. Biochem. Parasitol.
20:215-224[Medline].
|
| 30. | Suzuki, Y., F. K. Conley, and J. S. Remington. 1989. Importance of endogenous interferon-gamma in prevention of toxoplasmic encephalitis in mice. J. Immunol. 145:4185-4191[Abstract]. |
| 31. |
Suzuki, Y.,
Q. Yang,
F. K. Conley,
J. S. Abrams, and J. S. Remington.
1994.
Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis.
Infect. Immun.
62:2773-2778 |
| 32. |
Woodman, J. P.,
I. H. Dimier, and D. T. Bowl.
1991.
Human endothelial cells are activated by IFN- to inhibit Toxoplasma gondii replication: inhibition is due to a different mechanism from that existing in mouse macrophages and human fibroblasts.
J. Immunol.
147:2017-2023.
|
Infection and Immunity, October 1998, p. 4989-4993, Vol. 66, No. 10
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Delair, E., Creuzet, C., Dupouy-Camet, J., Roisin, M.-P.
(2009). In Vitro Effect of TNF-{alpha} and IFN-{gamma} in Retinal Cell Infection with Toxoplasma gondii. IOVS
50: 1754-1760
[Abstract] [Full Text] -
Melzer, T., Duffy, A., Weiss, L. M., Halonen, S. K.
(2008). The Gamma Interferon (IFN-{gamma})-Inducible GTP-Binding Protein IGTP Is Necessary for Toxoplasma Vacuolar Disruption and Induces Parasite Egression in IFN-{gamma}-Stimulated Astrocytes. Infect. Immun.
76: 4883-4894
[Abstract] [Full Text] -
Carruthers, V. B., Suzuki, Y.
(2007). Effects of Toxoplasma gondii Infection on the Brain. Schizophr Bull
33: 745-751
[Abstract] [Full Text] -
Lieberman, L. A., Cardillo, F., Owyang, A. M., Rennick, D. M., Cua, D. J., Kastelein, R. A., Hunter, C. A.
(2004). IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-12. J. Immunol.
173: 1887-1893
[Abstract] [Full Text] -
Aline, F., Bout, D., Dimier-Poisson, I.
(2002). Dendritic Cells as Effector Cells: Gamma Interferon Activation of Murine Dendritic Cells Triggers Oxygen-Dependent Inhibition of Toxoplasma gondii Replication. Infect. Immun.
70: 2368-2374
[Abstract] [Full Text] -
Silva, N. M., Rodrigues, C. V., Santoro, M. M., Reis, L. F. L., Alvarez-Leite, J. I., Gazzinelli, R. T.
(2002). Expression of Indoleamine 2,3-Dioxygenase, Tryptophan Degradation, and Kynurenine Formation during In Vivo Infection with Toxoplasma gondii: Induction by Endogenous Gamma Interferon and Requirement of Interferon Regulatory Factor 1. Infect. Immun.
70: 859-868
[Abstract] [Full Text] -
Schluter, D., Deckert, M., Hof, H., Frei, K.
(2001). Toxoplasma gondii Infection of Neurons Induces Neuronal Cytokine and Chemokine Production, but Gamma Interferon- and Tumor Necrosis Factor-Stimulated Neurons Fail To Inhibit the Invasion and Growth of T. gondii. Infect. Immun.
69: 7889-7893
[Abstract] [Full Text] -
Jakel, T., Wallstein, E., Muncheberg, F., Archer-Baumann, C., Weingarten, B., Kliemt, D., Mackenstedt, U.
(2001). Binding of a Monoclonal Antibody to Sporozoites of Sarcocystis singaporensis Enhances Escape from the Parasitophorous Vacuole, Which Is Necessary for Intracellular Development. Infect. Immun.
69: 6475-6482
[Abstract] [Full Text] -
Halonen, S. K., Taylor, G. A., Weiss, L. M.
(2001). Gamma Interferon-Induced Inhibition of Toxoplasma gondii in Astrocytes Is Mediated by IGTP. Infect. Immun.
69: 5573-5576
[Abstract] [Full Text] -
Freund, Y. R., Zaveri, N. T., Javitz, H. S.
(2001). In Vitro Investigation of Host Resistance to Toxoplasma gondii Infection in Microglia of BALB/c and CBA/Ca Mice. Infect. Immun.
69: 765-772
[Abstract] [Full Text] -
Zhang, Y. W., Halonen, S. K., Ma, Y. F., Wittner, M., Weiss, L. M.
(2001). Initial Characterization of CST1, a Toxoplasma gondii Cyst Wall Glycoprotein. Infect. Immun.
69: 501-507
[Abstract] [Full Text] -
Halonen, S. K., Weiss, L. M.
(2000). Investigation into the Mechanism of Gamma Interferon-Mediated Inhibition of Toxoplasma gondii in Murine Astrocytes. Infect. Immun.
68: 3426-3430
[Abstract] [Full Text] -
Yap, G. S., Sher, A.
(1999). Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-gamma - and Tumor Necrosis Factor (TNF)-alpha -dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii. JEM
189: 1083-1092
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»