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Previous Article | Next Article 
Infection and Immunity, January 2000, p. 407-410, Vol. 68, No. 1
0019-9567/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Toxoplasma gondii Infection Induces Gene Expression
and Secretion of Interleukin 1 (IL-1), IL-6, Granulocyte-Macrophage
Colony-Stimulating Factor, and Intercellular Adhesion Molecule 1 by
Human Retinal Pigment Epithelial Cells
Chandrasekharam N.
Nagineni,1
Barbara
Detrick,2,
and
John
J.
Hooks1,*
Laboratory of Immunology, National Eye
Institute, National Institutes of Health, Bethesda, Maryland
20892,1 and Department of Pathology, The
George Washington University Medical Center, Washington, D.C.
200372
Received 19 July 1999/Returned for modification 9 September
1999/Accepted 11 October 1999
 |
ABSTRACT |
We have used human retinal pigment epithelial (HRPE) cultures to
investigate the primary cellular responses of retinal resident cells to
intracellular Toxoplasma gondii replication. At 4 days postinoculation, when all of the cells were infected, the secretion of
interleukin 1
(IL-1), IL-6, granulocyte-macrophage
colony-stimulating factor (GM-CSF), and intercellular adhesion molecule
1 (ICAM-1) was augmented by 23-, 10-, 8-, and 5-fold, respectively,
over the control. Northern and reverse transcriptase PCR analyses
showed significant upregulation of steady-state levels of mRNA for
IL-1, IL-6, GM-CSF, and ICAM-1. The secretion of these molecules by HRPE cells may play a critical immunoregulatory role in the
pathophysiological processes associated with T. gondii-induced retinochoroiditis.
| |
TEXT |
Retinochoroiditis caused by
Toxoplasma gondii during ocular toxoplasmosis results in
inflammation and disorganization of the retina, occasionally leading to
severe loss of vision (11, 20, 23, 30). The intensity of
damage to the retina and choroid depends on the severity of the
infection and the associated inflammatory reaction (11, 13,
20). Inflammatory cells, predominantly macrophages and
lymphocytes, infiltrate the retina, the subretinal space, and the
vitreous (6, 11, 20). In the severe form of T. gondii-induced uveitis, destruction of large segments of the outer
retina and pigment epithelium is observed (6, 9, 13, 24).
Within the retina, lysosomal and other autolytic enzymes released by
inflammatory cells are thought to contribute to the pathogenic
mechanisms of retinal tissue damage (6, 11).
Retinal pigment epithelium (RPE), an integral part of the neuroretina
in the posterior pole of the eye, acts as a barrier between the highly
vascularized choroid and the retina with a complex architecture of
neuronal cells (2, 31). In addition to its role in the
transport of metabolites between retina and choroid, the RPE
phagocytose the shed outer segments of retinal rods and cones (2,
31). Many of these activities of the RPE are essential for the
structural and functional integrity of the retina and choroid. The RPE,
because of its critical location and physiological activities, is
constantly subjected to contact with various infectious agents and
inflammatory mediators (12, 14).
Tachyzoites of T. gondii injected into the peritonial
cavities of mice were thought to reach the retina via both choroidal and retinal circulation (8, 21, 26). In a rabbit model, injection of tachyzoites into the suprachoroidal space resulted in
outer retinal lesions and localized foci of retinal pigment epitheliosis within 48 h. This suggests the crossing of the
parasite through the RPE-Bruchs membrane barrier from the choroid to
the retina (27). Histopathological examination of the eyes
of patients with toxoplasma-induced retinochoroiditis revealed the
presence of free tachyzoites and cysts in the RPE and the retina
(9, 19, 24). Hence, studies of the mechanisms of T. gondii replication within retinal cells and the responses of the
host cells to parasite invasion would be valuable in understanding the
immunopathological basis of retinochoroiditis. Therefore, we have
investigated the responses of human RPE (HRPE) cells in the secretion
of immunologically relevant molecules upon parasite invasion and
intracellular replication.
Infection of HRPE cultures with T. gondii.
Primary
cell lines of HRPE were prepared from human donor eyes and propagated
as described previously (15). HRPE cultures at passages 6 to
12 were used for the experiments reported in this study. Tachyzoites of
T. gondii (RH strain), grown in HRPE cultures, were prepared
for inoculation as previously described (17). The cultures
were washed twice with serum-free medium and inoculated with
tachyzoites of T. gondii (0.5 ml/well in 24-well plates) at
a multiplicity of infection (MOI) of 5. Supernatant fluids from
duplicate wells of control (uninfected) and T. gondii-infected cultures were collected at various times (8, 24, 48, 72, and 96 h) postinoculation (p.i.) and frozen until used for
analysis. We have selected an MOI of 5 for T. gondii
inoculation studies, since it results in uniform infection of HRPE cell
layers. Cultures infected at an MOI of 1 were not uniformly infected,
whereas cultures infected at an MOI of 10 were rapidly destroyed.
IL-1, IL-6, GM-CSF, and ICAM-1 secretion by T. gondii-infected HRPE cells.
Culture supernatant fluids from
uninfected and T. gondii-infected HRPE cells were clarified
by centrifugation for 5 min at 13,000 × g in a
Microfuge. Levels of interleukin 1 (IL-1), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and intercellular adhesion molecule 1 (ICAM-1) in the culture supernatant fluids were determined by enzyme immunoassays using commercial kits
(Biosource, Camarillo, Calif., and R & D Systems, Minneapolis, Minn.).
Since low levels of IL-1 were detected in the media, an
ultrasensitivity kit (R & D Systems) with a detection range of 0.125 to
8 pg/ml was used. Results obtained from batches of the cultures grown
under similar conditions were used for the statistical analysis of the
data for any given experiment.
The time course of IL-1, IL-6, GM-CSF, and ICAM-1 secretion by
T. gondii-infected HRPE cells is shown in Fig.
1. T. gondii infection of HRPE
cells resulted in significant enhancement (P < 0.005)
in the secretion of IL-1 (control, 0.5 pg/ml, versus T. gondii, 11.5 pg/ml), IL-6 (control, 259.6 pg/ml, versus T. gondii, 2,476.3 pg/ml), GM-CSF (control, 35.4 pg/ml, versus
T. gondii, 291.8 pg/ml), and ICAM-1 (control, 7.8 ng/ml,
versus T. gondii, 35.3 ng/ml) at 4 days p.i. No significant
changes in the levels of these molecules in HRPE cultures incubated
with heat-killed T. gondii were observed (data not shown).
The secretion of tumor necrosis factor alpha, IL-4, IL-10, IL-12, and
IL-15 was not observed in control and T. gondii-infected
HRPE cells.
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FIG. 1.
Secretion of IL- (A), IL-6 (B), GM-CSF (C), and
ICAM-1 (D) by T. gondii-infected HRPE cells. Cell culture
supernatant fluids were collected at indicated p.i. times, and the
levels of IL-1, IL-6, GM-CSF, and ICAM-1 were determined by
enzyme-linked immunosorbent assay. The lower limits of detection were
0.13 pg/ml (IL-1), 10 pg/ml (IL-6), 15.6 pg/ml (GM-CSF), and 1.6 ng/ml (ICAM-1). Results are the means ± standard error for six
experiments, each with duplicate samples.
|
|
T. gondii-infected HRPE cells upregulate IL-1, IL-6,
GM-CSF, and ICAM-1 mRNA levels.
We next evaluated the steady-state
levels of IL-1, IL-6, ICAM-1, and GM-CSF mRNA in T. gondii-infected HRPE cultures to determine if the enhanced
secretion of these molecules was associated with the elevated levels of
mRNA. HRPE cells grown to confluence in 100-mm culture dishes were
inoculated with tachyzoites of T. gondii at an MOI of 5. After 1, 2, and 3 days of incubation, total cellular RNA from the
uninfected, T. gondii-infected, and
incubated-with-heat-killed (dead) T. gondii HRPE cultures
was prepared with extraction medium (RNA Stat-60; TEL-TEST,
Friendswood, Tex.). The integrity and purity of the RNA preparations
were checked by UV spectrum analysis and agarose gel electrophoresis.
RNA was fractionated by electrophoresis on 1% formaldehyde agarose
gels, transferred to nylon membranes, and immobilized by UV
cross-linking. Human IL-6 (15), ICAM-1 (16), and
GM-CSF (clone GMCSF, pCSF-1; American Type Culture Collection,
Manassas, Va.) cDNA probes were labeled by the random primer method
with digoxigenin-dUTP (Dig DNA labeling and detection kit; Boehringer
Mannheim, Indianapolis, Ind.). Following standard protocols of
hybridizations, membranes were washed twice with 2× SSC-0.1% sodium
dodecyl sulfate (1× SSC is 0.15 M NaCl plus 0.015 M sodium citrate) at
room temperature for 5 min, followed by two washes with 0.1×
SSC-0.1% sodium dodecyl sulfate at 68°C for 15 min each. The
hybridization signals were detected with antidigoxigenin alkaline
phosphatase conjugate and the chemiluminescence substrate CSPD.
IL-6 mRNA was not detectable in untreated cells and in cells incubated
with dead T. gondii (Fig. 2A,
top). At day 1 p.i., an IL-6 mRNA band was clearly detected and
the intensity of the band increased at days 2 and 3 p.i. The same
blot was stripped and used for hybridization with a digoxigenin-labeled
ICAM-1 cDNA probe. Faint bands were seen in untreated cells and cells
incubated with heat-killed T. gondii (Fig. 2A, middle).
ICAM-1 hybridization signals at days 1, 2, and 3 p.i. exhibit the
presence of intense bands, indicating the increase in ICAM-1 mRNA. The
panel showing the 28S RNA of ethidium bromide-stained RNA gel indicates
that total RNA loaded in the lanes of the control and dead T. gondii are of similar intensity to that of the bands in the lanes
of T. gondii, days 1, 2, and 3 p.i. Northern blot
analysis for GM-CSF mRNA is shown in Fig. 2B. In untreated and
dead-T. gondii-incubated cultures, a faint band is seen,
indicating low background levels of GM-CSF mRNA in uninfected cells. A
clear band is seen at day 1 p.i., and the intensity of the band
significantly increased at days 2 and 3 p.i. The gel of 28S RNA is
shown to indicate that equivalent amounts of total RNA were loaded in
all the lanes of the gel.
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FIG. 2.
Northern blot analyses of the expression of IL-6 and
ICAM-1 (A) and GM-CSF (B) mRNA in T. gondii-infected HRPE
cells. Total cellular RNA isolated from HRPE cells at indicated time
points were subjected to Northern blot analysis. The arrows indicate
the positions of IL-6 (1.3 kb), ICAM-1 (3.3 kb), and GM-CSF (0.8 kb)
mRNA. Lanes: control, uninfected cells incubated for 3 days; T. gondii, days 1, 2, and 3, cultures infected with T. gondii and total RNA prepared 1, 2, and 3 days p.i., respectively;
dead T. gondii, cells incubated for 3 days with heat-killed
T. gondii. The bottom panel shows the intensity of the 28S
RNA band of an ethidium bromide-stained RNA gel.
|
|
Analysis of IL-1 mRNA expression by RT-PCR.
Initial
attempts to demonstrate the expression of IL-1 mRNA by Northern blot
analysis were unsuccessful. This may be due to the low levels of
IL-1 mRNA corresponding to the low levels of IL-1 secreted by
T. gondii-infected HRPE cells. Therefore, we used the more
sensitive reverse transcriptase (RT)-PCR method for the amplification
of IL-1 mRNA. Total cellular RNA from the control and infected
cultures was prepared as described for Northern blot analysis. An RNA
PCR kit and GeneAmp PCR System 9600 (Applied Biosystems Division,
Perkin-Elmer, Foster City, Calif.) were used. RNA was reverse
transcribed to cDNA by incubating it with oligo(dT)16 as
the RT primer and MuLV RT for 15 min at 42°C and 5 min at 99°C, followed by 5 min at 5°C. cDNAs synthesized were amplified by PCR in
the presence of specific primers for GAPDH (glyceraldehyde-3-phosphate dehydrogenase) or IL-1 (Continental Laboratory Products, San Diego,
Calif.) in the presence of AmpliTaq DNA polymerase. Samples were heated for 105 s at 95°C and amplified for 30 cycles at
95°C for 15 s and 60°C for 30 s, followed by final
extension for 7 min at 72°C. PCR products were separated on an
ethidium bromide-containing agarose gel and photographed under UV light.
Faint bands are visible in both untreated and dead-T.
gondii-incubated cultures, suggesting basal levels of IL-1 mRNA
(Fig. 3). The intensity of the bands of
PCR products in T. gondii-infected cultures significantly
increased at days 1, 2, and 3 p.i. The lower panel shows the bands
of PCR products amplified with GAPDH primers that had the same total
RNA preparations as those in the upper panel.
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FIG. 3.
RT-PCR analyses of IL-1 and GAPDH mRNA expression in
T. gondii-infected HRPE cells. Total RNA (1 µg) was used
for reverse transcription and amplification (30 cycles) in a single
tube in an RNA PCR kit. Descriptions of samples loaded in the lanes are
the same as those given for Fig. 2. The sizes of IL-1 and GAPDH PCR
products are 331 and 600 bp, respectively.
|
|
Conclusions.
Results obtained in the present study show that
HRPE cells respond to T. gondii infection by secreting IL-1,
IL-6, GM-CSF, and ICAM-1. Levels of these cytokines increase
progressively with time (Fig. 1) and in correlation with the number of
host cells infected as well as with the intracellular parasite load.
Secretion of IL-1, IL-6, GM-CSF, and ICAM-1, but not nitric oxide, by
T. gondii-infected HRPE cells (17) suggest that
elevated secretion of inflammatory molecules by T. gondii is
not due to nonspecific injury to the cells. It should be emphasized
that HRPE cells are incubated in serum-free medium during T. gondii infection studies, and therefore, no stimulating agents or
serum factors are responsible for the induction of and/or interference
with the cytokine secretion. Upregulation of mRNAs and the secretion of
IL-1, IL-6, GM-CSF, and ICAM-1 by T. gondii-infected HRPE
cells in cultures, but not by HRPE cells incubated with heat-killed
T. gondii, indicate that the stimulus for the activation of
inflammatory molecule secretion is derived from the interaction between
host cells and the parasite at different stages of parasite
infiltration, parasite intracellular replication, and/or release of
parasite secretion and degradation products (3, 18).
In vitro cell culture models of T. gondii infection have
demonstrated altered cellular responses during parasite infection. Secretion of IL-1, IL-6, and GM-CSF was observed in mouse brain astrocyte and microglial cell cultures infected with virulent and
avirulent T. gondii strains (7). In these
experiments, heat killing of the parasites abolished the
cytokine-inducing activity. However, in another study, no significant
induction of IL-1
, IL-6, and tumor necrosis factor alpha mRNA was
observed in human astrocytoma and macrophage cell lines infected with
virulent or avirulent RH or prugniaud strains (22). The
present study shows that HRPE cells contribute to the production of
proinflammatory cytokines within the ocular microenvironment during
T. gondii infection. Differential responses of various cell
types to T. gondii infection could be due to a combination
of parasite trigger and inherent properties of the host cells.
Interactions of host cells and parasite may result in the activation of
appropriate signal transduction pathways, resulting in transcriptional
upregulation. Further studies are required to identify specific
mechanisms and transcription factors involved in T. gondii-induced pathogenesis.
The role of cytokines and adhesion molecules in uveitis and other
inflammatory diseases of the eye is well documented (5, 28).
Levels of IL-6 and soluble ICAM-1 are found to be elevated in the
vitreous fluids of patients with uveitis and proliferative vitreoretinal disorders, respectively (1, 4). Increased expression of ICAM-1 on the RPE of uveitis patients (29) and on epiretinal membranes formed during proliferative vitreoretinopathy (10) have also been reported. Further, direct intravitreal
injection of IL-1 was shown to induce uveitis in an animal model
(25). Together, these observations indicate that IL-1, IL-6,
and ICAM-1 play critical roles in intraocular inflammatory diseases.
The secretion of IL-1, IL-6, GM-CSF, and ICAM-1 by HRPE cells in
response to T. gondii infection, as shown in this study, may
have multiple roles under in vivo conditions. Elevated production of
these factors and other molecules by T. gondii-infected
resident cells may initiate local immune reactivity during primary
infections and during recurrent reactivation episodes in
toxoplasma-induced retinochoroiditis.
| |
ACKNOWLEDGMENTS |
We thank Charles Egwuagu, Kumar Srinivasan, and Laura Chesky for
critical reading of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Immunology and
Virology Section, Laboratory of Immunology, National Eye Institute, Building 10, Room 6N 228, National Institutes of Health, Bethesda, MD
20892. Phone: (301) 496-6578. Fax: (301) 480-2988. E-mail: jjhooks{at}helix.nih.gov.
Present address: Department of Pathology, Johns Hopkins University
School of Medicine, Baltimore, Md.
Editor:
J. M. Mansfield
| |
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Infection and Immunity, January 2000, p. 407-410, Vol. 68, No. 1
0019-9567/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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