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in the Mouse Placenta During Listeria monocytogenes Infection1
* Center for the Study of Reproductive Biology and Women’s Health, Department of Developmental and Molecular Biology and
Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY 10461; and
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a cytokine required for the resolution of this infection.
These data suggest that IDO plays a role in resolving bacterial
infection in the placenta while at the same time maintaining a barrier
to T cells whose presence might result in fetal
rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this view of the placenta as an immuno-suppressed environment, it is difficult to understand how infection is fought at the maternal-fetal interface. To explore this question, we have recently used Listeria monocytogenes infection of the placenta as a probe for the maternal immune response. This Gram-positive facultative intracellular bacterium replicates systemically in macrophages, cells that also form the first line of defense against this pathogen. Consequently, the macrophage-rich organs such as liver and spleen are the sites for bacterial replication (8). However, during pregnancy L. monocytogenes also has a predilection for replication at the maternal-fetal interface where it is responsible for high incidences of fetal morbidity and mortality in humans (9). In Murids, this bacterium replicates primarily in the decidua basalis (10). Interestingly, in these species macrophages are present in high number in the myometrium and undecidualized endometrium (11, 12, 13), yet are excluded from the decidua basalis and most of the fetally derived placenta (10, 14).
CSF-1, the primary growth factor for macrophages, is synthesized to
very high concentrations at the maternal-fetal interface by the uterine
epithelium (15, 16). Apart from the macrophages present in
the undecidualized stroma, trophoblast express the CSF-1R suggesting
that these are also target cells. Because macrophages are not present
at this site, we suggested that trophoblast acts in lieu of the
macrophage to regulate the local immune response at the maternal-fetal
interface (17). To test this hypothesis, we exploited a
mouse mutant that carries a null mutation in the CSF-1 gene
(osteopetrotic, Csf1op). Mice homozygous
for this mutation were unable to mount an effective immune response to
L. monocytogenes either systemically or locally in the
placenta. In the former case, most of the deficiency was ascribed to
the inability to synthesize IFN- (18), while in the
latter there was a complete failure to recruit neutrophils to the
decidua basalis (17). This was due to the inability
of trophoblast, in the absence of CSF-1, to synthesize the mouse
neutrophil chemoattractants macrophage-inflammatory protein (MIP)-2 and
KC (IL-8 homologs). Consequently, CSF-1 regulated trophoblast appear to
act like macrophages in regulating an effective immune response at the
maternal-fetal interface without activating an anti-fetal
response.
Extrapolating from the work on macrophages where IDO expression is
found in macrophages that have been differentiated in the presence of
CSF-1 (5), the high level of CSF-1 at the maternal-fetal
interface suggests that this growth factor regulates IDO expression in
trophoblast and that this might be important during Listerial
infection. Consistent with this is the IDO expression in syncytial
trophoblast in humans (19, 20). We sought to test this
hypothesis by analyzing IDO expression in CSF-1-deficient placenta,
identifying the cell type expressing this enzyme and to ask whether
this regulation plays a role during Listerial infection. We
demonstrated that IDO was not expressed in mouse trophoblastic cells
but in stromal cells of the metrial gland and decidua basalis. In
this study, this enzyme was induced following infection by L.
monocytogenes in an IFN-- but not CSF-1-dependent manner.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice were housed in the barrier facility at the Albert Einstein
College of Medicine’s vivarium (Bronx, NY) under normal light
conditions and were fed ad libitum. Mice 3–5 mo of age were
mated and the day the vaginal plug was found was counted as day 1. Mice
were killed on different days of gestation depending upon the day of
infection as stated in the text. To study CSF-1 responses, females
heterozygous or homozygous for the CSF-1 null mutation,
Csf1op, were mated with
Csf1opCsf1op males. The
Csf1opCsf1op mouse diet
consisted of powdered chow and infant formula (Enfamil; Mead Johnson,
Evansville, IN) and the mutation was identified as described before
(13). Mouse strains with targeted deletions in the genes
for IFN- (21) and TNFR1 (22) were
similarly used to investigate the mechanism of IDO induction. Both
strains have been backcrossed onto the C57BL/6 background (The Jackson
Laboratory, Bar Harbor, ME); therefore, wild-type C57BL/6 was used as
the control strain.
For Listeria studies, pregnant females were infected i.v. on day 10 or 14 of gestation, as indicated, through the lateral tail vein with 104 L. monocytogenes and subsequently killed after 24, 48, or 72 h of infection. L. monocytogenes, strain EGD, was grown to log phase in tryptose phosphate broth (Difco, Detroit, MI) and stored in aliquots at -70°C. Bacterial titer was calculated by plating duplicate serial dilutions of bacteria stock on tryptose phosphate agar plates and counting colonies after 24 h. All studies were performed under National Institutes of Health guidelines for the care and treatment of experimental rodents.
Northern blotting
Total RNA was isolated using the guanidium thiocyanate method
(23). Total RNA was separated by electrophoresis (20
µg/lane) in a 1.0% formaldehyde-agarose gel and then transferred to
a nylon transfer membrane (Schleicher & Schuell, Keene, NH) as
described (24). The blots were probed with gel-purified
[32P]dCTP-labeled cDNA probes (Prime-It RmT;
Stratagene, Cedar Creek, TX). IDO cDNA was prepared by RT-PCR using
forward (GTA CAT CAC CAT GGC GTA TG) and reverse (GCT TTC GTC AAG TCT
TCA TTG) oligonucleotide primers (4); PCR products of the
expected size (740 bp) were sequence verified. Membranes were exposed
to a Storage Phoshor Screen (Molecular Dynamics, Sunnyvale, CA) and
measurements were made using the Storm phosphoimager (Molecular
Dynamics). mRNA was quantified using ImageQuant software (Molecular
Dynamics). Membranes were subsequently stripped and reprobed for
-actin for normalization.
Immunohistochemistry
Placentae were harvested on days 10, 12, and 14–17 of pregnancy (no infection) and over the course of Listerial infection (days 11–12 and 15–16 of pregnancy equals 24–48 h of infection), fixed in 10% buffered formalin for 24 h and stored in 70% ethanol at 4°C. Tissues were subsequently processed for paraffin sectioning. Five-micrometer sections were immunostained with rabbit anti-mouse IDO antiserum (1/400 dilution; 1 h at room temperature) (25) and developed using a peroxidase detection kit (Vector Laboratories, Burlingame, CA). The IDO immunohistochemistry protocol was kindly provided by Dr. N. Hunt (Department of Pathology, University of Sydney, New South Wales, Australia). Briefly, following standard deparaffinization steps, slides were boiled in citric acid buffer for Ag retrieval and then blocked with normal goat serum in blocking buffer (0.1 M Tris (pH 7.5), 0.15 M NaCl, 0.5% BSA). In between primary and secondary Ab incubations and peroxidase development, slides were washed with 0.1 M Tris buffer (pH 7.5) containing 0.3 M NaCl and 0.5% Tween 20; the high NaCl concentration was necessary to avoid background staining. Nonspecific rabbit IgG (5 µg/ml) was used as a primary Ab negative control. Subsets of slides were double stained with Periodic-Acid Schiff (Sigma Diagnostics, St. Louis, MO) to identify granules of uterine NK (uNK) cells and basement membranes. All sections were counterstained with Gill No. 3 Hematoxylin Solution (Sigma Diagnostics).
Western blotting
Protein was extracted from tissues by homogenization using the Tissue Tearor (Biospec Products, Bartlesville, OK) in buffer containing 5% IGEPAL CA-630, 6 mM deoxycholic acid, 8% SDS in PBS, and mammalian protease inhibitors on ice (all chemicals from Sigma Diagnostics); supernatants were frozen at -70°C until time of assay. Protein concentrations were measured using Bradford Reagent (Bio-Rad, Hercules, CA). Protein samples (50 µg protein/lane) were separated by SDS-PAGE and immunoblotted using IDO antisera (1/2000 dilution) overnight at 4°C and then incubated with HRP-conjugated anti-rabbit IgG (Santa Cruz Biotechnology, Santa Cruz, CA) at room temperature for 1 h. The membrane was developed with ECL Western Blotting detection reagent (Amersham Biosciences, Piscataway, NJ). Protein was quantified using ImageQuant software (Molecular Dynamics). Membranes were stripped and reprobed with anti-GAPDH Ab for normalization.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that IDO expression peaks at around day 10 of
pregnancy and falls until it is barely detectable at day 18
(25). To confirm this in our mouse strain, Northern blots
of total RNA isolated on days 9, 10, 12, 14, 15, 16, and 17 of
pregnancy in +/Csf1op females were probed
with a radiolabeled IDO cDNA (Fig. 1).
IDO mRNA expression (normalized to -actin RNA levels) was highest
between days 9 and 10 of pregnancy. However, by day 12, expression had
begun to decline and continued to do so until expression was below the
level of detection on day 17 (Fig. 1).
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It has been reported that IDO activity is present in the syncytial trophoblastic layer of the placenta in humans (19, 20). To determine whether a similar localization was found in mice, we performed immunohistochemistry with an anti-IDO Ab at day 14 of pregnancy when all placental layers are formed and fully demarcated. Protein expression was not evident in the trophoblastic layers or elsewhere in the fetal compartment. However, strong immunoreactivity was found in the metrial gland and decidua basalis (Fig. 2, A and B). This distribution did not change at least until day 17 of pregnancy (data not shown). These maternal compartments are populated by numerous uNK cells. Thus, to determine whether these cells were the source of IDO the immunostained sections were counterstained with Periodic Acid Schiff (PAS) that identifies the characteristic NK granules (26). This double stain indicated that uNK cells were negative for IDO which instead was localized to stromal cells dispersed throughout these two regions (Fig. 2C). Moreover, IDO-positive cells did not line the vasculature in these regions (Fig. 2D). Staining for a neutrophil marker, Gr-1, revealed only scattered cells in the decidua basalis usually associated with the vasculature. Macrophages identified with anti-F4/80 Ab were not found in the placenta as has been extensively reported before (10, 13, 14, 17), although they could be readily seen in the undecidualized stroma adjacent to the luminal epithelium between the implantation sites. Although double staining was not performed, the very few neutrophils present identified by morphology were negative for IDO (Fig. 2I, see below), and there was no staining in subepithelial stroma occupied by macrophages (data not shown). As a positive control, IDO was detected in macrophage-like cells throughout the white pulp of the spleen as previously reported (Fig. 2E). No immunostaining was detected with a control rabbit antisera (Fig. 2F).
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In conclusion, hemopoietic cells such as neutrophils, uNK cells, and macrophages do not express IDO in the uterus, nor is IDO expressed in trophoblastic cells. However, there is abundant expression of IDO in the stromal cells of the metrial gland and decidua basalis.
Placental IDO expression increases during L. monocytogenes infection
With the normal pattern of IDO established, we next determined if this expression was altered by an infection with L. monocytogenes. +/Csf1op female mice were infected with L. monocytogenes on day 14 of pregnancy. Placentae were harvested at 24, 48, and 72 h after injection with noninfected placentae serving as controls. Total RNA was isolated and IDO expression was analyzed by Northern blot (Fig. 3A). Placental IDO transcripts were unchanged 24 h (day 15) after infection but exhibited a 3.5-fold increase at 48 h (day 16). This was maintained through to 72 h (day 17) of infection. Thus, in the face of infection, IDO mRNA persists for longer than in uninfected mice.
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We also analyzed the expression pattern of IDO by immunohistochemistry in the utero-placental unit 24 and 48 h following infection either at day 10 or 14 of pregnancy. Expression was generally stronger following infection, consistent with the up-regulation of the enzyme in placental homogenates as detected by Western blotting. Overall, the distribution was the same as in the uninfected state with stromal cells in the decidual and metrial gland areas expressing IDO. However, notably the endothelial cells lining both arteries and veins in the decidua and metrial gland, which were negative in the uninfected state (Fig. 2, J and K), were now positive 48 h after infection on either day 10 (Fig. 2L) or 14 (data not shown) of gestation.
IFN- but not CSF-1 nor TNF-
regulates IDO expression in the
placenta
IDO expression is found in macrophages that have differentiated in
the presence of CSF-1 (5). CSF-1 concentrations reach very
high levels in the placenta and the CSF-1R is expressed on
trophoblastic cells (16, 24). Therefore, we questioned
whether IDO expression was regulated directly or indirectly by CSF-1 by
comparing expression in mice heterozygous or homozygous for the CSF-1
null mutation, Csf1op (13).
Total RNA was isolated from
Csf1op/Csf1op
(CSF-1 null) and +/Csf1op (CSF-1 positive)
placentae on day 14 of pregnancy. Northern blot analysis for IDO
expression, normalized to -actin expression, demonstrated identical
RNA expression levels between +/Csf1op and
Csf1op/Csf1op
placentae (Fig. 4A). Following
infection at day 10 with L. monocytogenes, IDO transcript
(Fig. 4B) and protein level (Fig. 4C) were
elevated in the placenta even in the absence of CSF-1. Thus, and
consistent with the restriction of CSF-1R expression to trophoblastic
cells (24), IDO is not regulated in the placenta by CSF-1
either during normal pregnancy nor following infection.
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(27, 28). We have previously shown
that both IFN- and TNF- are up-regulated in the placenta
following L. monocytogenes infection (17). To
determine whether these cytokines regulate its expression in vivo, we
analyzed IDO expression in the placenta of mice carrying null mutations
in the IFN- and TNFR1 genes. These null mutants were infected at day
10 of gestation and placenta analyzed for IDO transcripts and protein
on day 12 of gestation. C57BL/6 mice onto which background the null
mutations have been backcrossed served as the control strain. In both
the TNFR1 knockout (KO) mice and IFN- KO mice, IDO expression was
apparent on day 12 of gestation in the uninfected state (Fig. 5). By 48 h after L.
monocytogenes infection, IDO expression increased in the TNFR1 KO
mice to a comparable extent as in the C57BL/6 controls at both the
transcript and protein level (Fig. 5). However, no induction in IDO
expression was evident in the IFN- KO and both the transcript and
protein level remained at the baseline (Fig. 5).
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(Fig. 2N). Thus, the endothelium is
either a direct or indirect target of IFN- for the induction of
IDO.
In the systemic immune response to L. monocytogenes, to
achieve sterile eradiation a Th1 type response needs to be elicited.
Cytotoxic T lymphocytes would be disadvantageous to pregnancy and they
would need to be restrained from entering the placenta. Mellor and
colleagues (4) showed that inhibition of IDO resulted in a
T cell-mediated rejection of fetuses. Therefore, we questioned whether
the IFN- induction of IDO in the placenta was required to prevent T
cell influx. However, despite this lack of IDO induction during
L. monocytogenes infection in the IFN--deficient
placenta, immunohistochemistry using an anti-CD3-
Ab did not
detect significant T cell infiltration on sections up to 96 h
after infection (data not shown). Thus, IDO is regulated in vivo in the
placenta by IFN- following Listeria infection, but the
absence of this induction does not result in T cell
recruitment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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did not enhance bacterial clearance in the placenta in the
absence of CSF-1. Because CSF-1 also regulates KC synthesis in
macrophages, this suggests that this CSF-1-regulated signaling pathway
is sequestered by the trophoblast (31). In the human placenta as in the mouse, trophoblastic cells express the CSF-1R and there is a high concentration of ligand at all stages of pregnancy (32). Recent reports have shown IDO activity by trophoblastic cells, particularly syncytial trophoblasts, in human placentae (19, 20). This was confirmed in cultured primary trophoblastic cells, although the choriocarcinoma cell line BeWo is negative for this enzyme (33). IDO synthesis is found in macrophages that have been differentiated from monocytes in the presence of CSF-1 (5). These data suggest that the differentiation of trophoblastic cells in the presence of CSF-1 might be important for trophoblastic IDO expression. However, the current studies clearly show that in the mouse, IDO is not expressed in trophoblastic cells. Instead, immunohistochemical studies indicate that the source of IDO is mesenchymal cells distributed throughout the metrial gland and decidua basalis. These cells do not express the CSF-1R; therefore, it is not surprising that placental IDO expression is not regulated by CSF-1. It remains a possibility that CSF-1 is required for IDO expression in human trophoblasts where there is coincidence of CSF-1R and enzyme expression.
Elegant studies have shown that the inhibition of IDO with the
competitive inhibitor l-methyl-tryptophan leads to a T cell-mediated
rejection of allogenic fetuses (4). Interestingly, this is
mediated in part through the complement system (34). These
data suggest that an important role for IDO is to suppress T cell
responses during pregnancy. Evidence for IDO activity in macrophages
and dendritic cells, cells that primarily stimulate T cells, also
supports the idea that IDO may serve immune regulatory functions in
certain microenvironments (7, 35, 36). These effects are
probably mediated via actions of tryptophan metabolites inhibiting T
cell proliferation and inducing cell cycle arrest and/or apoptosis
(37, 38). Previously we noted that, in normal mice, there
was no increase in fetal wastage during Listeria infection
and the bacterium was cleared by 72 h (17). T cells
are not observed to infiltrate the decidua basalis or trophoblast
during Listeria clearance even in allogenic pregnancies as
has previously been reported by Redline and Lu (10).
However, this is also true in the IFN- KO mice even in the absence
of IDO induction, suggesting that basal levels of placental IDO are
sufficient to maintain a T cell barrier. Nevertheless, the observation
that IDO is found in the endothelium following L.
monocytogenes infection in normal mice suggests that this provides
a further barrier against T cell infiltration into the placenta.
In contrast to this suppressive role, increased IDO expression also provides a mechanism for tryptophan deprivation during inflammatory responses to pathogens. IDO induction in macrophages has been demonstrated during viral (39) and bacterial infection (40). High activity of IDO could aid the inhibition of bacterial growth since tryptophan is often an essential amino acid for bacteria. Most work investigating anti-bacterial effects of IDO have focused on the Chlamydia bacterium. Like Listeria, Chlamydia is an intracellularly growing bacterium. Although Chlamydia has a predilection for replicating in epithelial cells, it can also replicate in macrophages. Depletion of tryptophan in vitro by IDO drives the bacterium into a persistent altered life cycle in which the organism exists as an aberrant body (41). In the process of metabolizing tryptophan, IDO activity exerts antioxidant effects since the enzyme requires superoxide anion and generates several intermediate products that are potent radical scavengers as well as the energy generating NAD and NADP (42). It has also been suggested that the IDO-mediated removal of tryptophan reduces the synthesis of serotonin, a powerful vasconstrictive agent that is synthesized from typtophan (43). Consequently, the expression of IDO at the site of infection could result in the inhibition of bacterial replication as well as the removal of toxic oxygen radicals, a localized vasodilation and an increase availability of NAD and NADP for energy generation. All these processes would enhance a successful immune response and be protective to the tissue and that would be likely to enhance the resolution of infection in the placenta.
The mechanisms that regulate placental IDO expression have yet to be
fully defined; however, recent work by Kudo et al. (44)
suggests that IFN- stimulates enhanced IDO activity in human
placental explants. Similarly, IFN- up-regulates IDO activity in
macrophages (5) and several cell lines (45).
Our observation that IDO mRNA and protein is expressed in the IFN-
KO mouse during pregnancy suggests that there is no absolute need for
the cytokine during developmental expression of IDO. However, the
absence of IDO induction during Listeriosis in this mutant mouse does
indicate a critical role for IFN- in the ability to elevate
placental IDO expression during infection and for its expression in
endothelial cells within the utero-placental unit. This is consistent
with the up-regulation of IFN- in the placenta at 48 h after
infection and with the essential role of IFN- in systemic (46, 47) or placental (E. M. Barber and J. W. Pollard,
unpublished observations) responses to L. monocytogenes.
Similarly, studies using human aortic smooth muscle cells demonstrated
that treatment with IFN- increased IDO expression and enzymatic
tryptophan catabolism resulting in a dose-dependent inhibition of
Chlamydia pneumoniae replication
(40). In contrast, TNF- appears to not have a role in
placental IDO induction. Both developmental expression levels and
infection-associated inductions appear normal in TNFR1 null mutant
mice. This agrees with several reports that TNF- cannot induce IDO
alone but only enhances the effects of IFN- (48, 49).
In conclusion, data presented in this study do not support the
hypothesis that IDO is a CSF-1-regulated trophoblast product, rather
they demonstrate that the enzyme is produced by maternal stromal cell
populations in the metrial gland and decidua basalis. In addition,
we show an enhanced expression during Listeriosis that is regulated by
IFN-. These data suggest that IDO is capable of maintaining a T cell
barrier while enhancing the resolution of an infection in the
placenta.
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Acknowledgments |
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Footnotes |
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2 A.M.M. and E.M.B. contributed equally to this work.
3 Current address: Department of Medical Services, Organon Pharmaceuticals, 375 Mount Pleasant Avenue, West Orange, NJ 07052.
4 Address correspondence and reprint requests to Dr. Jeffrey W. Pollard, Department of Developmental and Molecular Biology and Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: pollard{at}aecom.yu.edu
5 Abbreviations used in this paper: IDO, indoleamine 2,3-dioxygenase; KO, knockout; MIP, macrophage-inflammatory protein; uNK, uterine NK; PAS, Periodic Acid Schiff.
Received for publication July 26, 2002. Accepted for publication November 6, 2002.
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References |
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genes. Science 259:1739. in human placental chorionic villi. Mol. Hum. Reprod. 6:369. interferon fails to induce expression of indoleamine 2,3-dioxygenase and does not control the growth of Chlamydophila abortus in BeWo trophoblast cells. Infect. Immun. 70:2690.+ dendritic cells. Int. Immunol. 14:65. interferon-induced indoleamine 2,3-dioxygenase activity. Infect. Immun. 68:6478. interferon-mediated chlamydial persistence. Infect. Immun. 62:3705., indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 5:2516.[Abstract]
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and lipopolysaccharide enhance interferon-induced tryptophan degradation and pteridine synthesis in human cells. Biol. Chem. Hoppe Seyler 370:1063.[Medline]
and lipopolysaccharide enhance interferon-induced antichlamydial indoleamine dioxygenase activity independently. J. Interferon Cytokine Res. 20:369.[Medline]This article has been cited by other articles:
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E. M. Barber, M. Fazzari, and J. W. Pollard Th1 Cytokines Are Essential for Placental Immunity to Listeria monocytogenes Infect. Immun., October 1, 2005; 73(10): 6322 - 6331. [Abstract] [Full Text] [PDF]
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P. H. Tan, S. C. Beutelspacher, S.-A. Xue, Y.-H. Wang, P. Mitchell, J. C. McAlister, D. F. P. Larkin, M. O. McClure, H. J. Stauss, M. A. Ritter, et al. Modulation of human dendritic-cell function following transduction with viral vectors: implications for gene therapy Blood, May 15, 2005; 105(10): 3824 - 3832. [Abstract] [Full Text] [PDF]
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E. M. Barber and J. W. Pollard The Uterine NK Cell Population Requires IL-15 but These Cells Are Not Required for Pregnancy nor the Resolution of a Listeria monocytogenes Infection J. Immunol., July 1, 2003; 171(1): 37 - 46. [Abstract] [Full Text] [PDF]
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