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Istituto di Microbiologia, Università di Messina, Facoltà di Medicina e Chirurgia, Messina, Italy
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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play a crucial role in antilisterial
resistance (4). In contrast, IL-4, a Th2-derived cytokine,
has been reported to increase susceptibility to infection (5, 6).
Recent studies indicate that cytokine production is profoundly altered
in the neonatal period and that these changes may be clinically
relevant. Neonatal lymphocytes from either mice (7) or
humans (8, 9, 10) show markedly decreased in vitro IFN-
production. In vivo IFN- responses to endotoxin are depressed in
neonatal mice and reach adult-like levels only at 30 days after birth
(11). In contrast, murine neonatal T cells produce higher
amounts of IL-4, relative to adult cells, after in vitro stimulation
(7). Collectively, these observations suggest that early
life may be associated with an imbalance between type 1 and 2
cytokines, which, in turn, may at least partially account for the
increased susceptibility of neonates to intracellular pathogens.
Little is known of the production of IL-10 in the neonatal period. This
cytokine is produced by T cells, macrophages, and B cells
(12, 13, 14), and has an important role in the regulation of
cell-mediated immunity. IL-10 can exert potent
anti-inflammatory activities both in vivo and in vitro, and
profoundly inhibits macrophage production of a number of
proinflammatory mediators including IL-1, IL-6, and TNF-
(15, 16, 17), while enhancing the expression of IL-1R
antagonist (18). In addition, IL-10 down-regulates Th1
activities, most likely by modulating several accessory cell functions
of monocytes/macrophages (19, 20). It has been suggested
that IL-10 enhances the growth of facultative intracellular pathogens
such as Brucella abortus (21),
Mycobacterium avium, and Mycobacterium bovis
(22, 23, 24).
The role of IL-10 in listeriosis is not entirely clear. Anti-IL-10 treatment resulted in increased bacterial replication and lethality late in the course of infection, after producing an early improvement (25). In another report, however, adult IL-10-deficient mice showed increased resistance to L. monocytogenes (26), while administration of r IL-10 severely decreased innate defenses against the organism (27). In view of the potential importance of IL-10, we examined the role of this cytokine in neonatal and adult murine listeriosis models. Specifically, we tested the hypothesis that IL-10 production is altered in neonatal mice infected with Listeria.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The L. monocytogenes strain used in the present study was a recent clinical isolate. Group B streptococcal (GBS)3 strain COH1 (type III) was kindly provided by Craig Rubens (University of Washington, Seattle). Killed bacteria were prepared from log-phase cultures in Todd-Hewitt broth (Difco, Diagnostic International Distribution, Milan, Italy) by heating at 80°C for 45 min, followed by extensive washing with distilled water and lyophilization.
The hybridoma SXC1, producing rat anti-mouse IL-10, was kindly provided by L. Romani (University of Perugia, Perugia, Italy). The hybridomas RA3-3A1/6.1, producing rat anti-mouse B cell surface glycoprotein B220 (ATTC TIB 146), and 53-7.313, producing rat anti-mouse CD5 (ATTC TIB 104) Abs, were obtained from the American Type Culture Collection (Manassas, VA). All of these mAbs were purified from culture supernatants, as described (28). Rat anti-mouse IL-10 IgG1 and CD19 mAbs were purchased from Genzyme (Cinisello Balsamo, Italy) and PharMingen (San Diego, CA), respectively. LPS from Salmonella enteritidis and rabbit C were obtained from Sigma Chimica (Milan, Italy). Normal rat IgM and IgG, used as controls, were obtained from normal serum samples by affinity chromatography on GammaBind G Sepharose (Pharmacia Biotech, Milan, Italy), as described (28).
Animals
BALB/c mice of different ages were used. Parental mice were
obtained from Harlan-Nossan (Milan, Italy) and housed in the animal
facilities of the Institute of Microbiology of the University of
Messina (Messina, Italy). Periodic examinations showed that the colony
was free from naturally occurring infections. All of the experiments
described in this work were approved by the appropriate local
authorities, and all of the procedures were in agreement with the
guidelines of the National Institutes of Health for handling of
laboratory animals. Females from timed matings were monitored closely,
and the date of delivery was recorded. Neonatal and adult mice were
defined as 
24 h and 56–62 day old, respectively. Pups from each
litter were randomly assigned to control or experimental groups. The
neonates were marked by positioning around hind legs of thin copper
wires obtained from the strands of standard electric cords. The pups
were kept with the mother for the entire duration of the
experiment.
Listeriosis model
Mice of different ages were infected s.c. with viable L. monocytogenes. Bacteria were grown in Todd-Hewitt broth to the mid log-phase, and kept frozen at -70°C until needed for inoculation in mice. Aliquots thawed at different times throughout the study all had the same numbers of viable bacteria. Thawed bacteria were diluted in PBS (0.01 M phosphate, 0.15 M NaCl, pH 7.2) to the desired concentrations. Twenty-five and five hundred microliters were used, respectively, to inoculate pups and adults. For lethality experiments, mice were observed every 24 h for 20 days. Deaths rarely occurred after 15 days. To calculate bacterial burden in organs, mice were killed by decapitation under ether anesthesia at various times after challenge, and the spleens and the livers were removed. The numbers of viable bacteria were calculated by plating serial dilutions of organ homogenates on tryptic soy agar, as described (29).
To measure circulating IL-10 levels, mice were killed by decapitation under ether anesthesia at various times after challenge with viable or killed L. monocytogenes. Mixed venous-arterial blood was collected in heparinized containers and centrifuged. Pooled plasma was stored at -70° until assayed for IL-10 concentrations.
Spleen cell cultures
Spleens from neonatal or adult mice were removed aseptically in
RPMI 1640 medium, and single cell suspensions were prepared by teasing
the organs with sterile forceps, as described (30). Spleen
cells from 10 neonatal mice were pooled for each experiment. Cells were
washed, resuspended in RPMI 1640 medium to a concentration of 2 x
106/ml, and seeded in 1-ml volumes in 24-well
plates. Cultures were stimulated with killed bacteria (50 µg/ml) or
LPS (10 µg/ml) and incubated at 37°C in 5%
CO2 for 24 h. IL-10 or IFN- levels were
measured in supernatants using commercial ELISA kits.
Cell separation experiments
To identify the cell types predominantly responsible for IL-10
production, spleen cells were separated by adherence. Cells were
resuspended in RPMI 1640 to a concentration of 2.5 x
106/ml, and 4 ml were dispensed to glass petri
dishes. After incubation for 2 h, nonadherent cells were removed
by three washings with RPMI 1640. Adherent cells were washed three
times with RPMI, exposed to 2 mM EDTA for 15 min at 4°C, and gently
resuspended with a scraper. Once recovered, adherent and nonadherent
cells were resuspended to a concentration of 2 x
106/ml. Cells were then cultured in 1-ml volumes
in 24-well plates for 24 h in the presence of the stimuli, as
described above. Adherent cells from either neonatal mice or adults
were >90% macrophages by either nonspecific esterase staining
(-naphtyl acetate esterase kit; Sigma) or phagocytosis of opsonized
Candida albicans (31). In selected experiments,
splenocytes were depleted from B lymphocytes or
CD5+ (Ly-1) B cells by anti-CD19,
anti-CD45, or anti-CD5 mAbs, respectively, in the presence of
rabbit C, as described (32). Briefly, single cell
suspensions were depleted from RBC with a lysing agent (Blood Cell
Lysing Buffer; Sigma) and resuspended to a concentration of 1 x
107/ml. Aliquots of these suspensions were mixed
with mAbs or control rat IgG (10 µg/ml) in the presence or in the
absence of rabbit C (diluted 1/10). After incubation at 37°C for 30
min, cells were washed, resuspended to a concentration of 2 x
106, and stimulated with heat-killed
Listeria, as described above. Preliminary experiments
excluded that the Ab or C concentrations used were capable, alone, of
causing cytotoxicity.
Cytokine measurements
IL-10 was measured in plasma or cell culture supernatants using
a commercial ELISA kit (Biosource, Camarillo, CA). The lower limit of
detection of the assay was 15 pg/ml. IFN- levels were measured in
culture supernatants with the Intertest- ELISA kit (Genzyme) with a
lower limit of detection of 5 pg/ml.
Expression of data and statistical analysis
Cytokine levels are expressed as means ± SDs of five independent observations, each conducted on a different sample. Samples below the detection levels were assigned a theoretical value of one-half the detection limit. Differences in cytokine levels and bacterial counts were assessed by one-way ANOVA and Student-Newman-Keuls test. Differences in lethality were assessed by Fisher exact test. With both tests, differences were considered significant when p values were <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In initial experiments, we compared the lethal effects of Listeria infection in neonatal and adult mice. The animals were injected s.c. with different doses of viable L. monocytogenes, and lethality was observed every 24 h. To cause significant lethality in the pups and in the adults, 10 and 2 x 107 CFU, respectively, were needed (data not shown). Calculated LD50 of L. monocytogenes were 2.5 x 101 and 5 x 107 CFU, respectively, in neonatal and adult mice. These data were in agreement with previous studies (33), and indicated that neonatal age is associated with a markedly increased susceptibility to L. monocytogenes infection in mice.
IL-10 plasma levels after challenge with L. monocytogenes
To assess whether neonatal susceptibility to L.
monocytogenes is associated with altered IL-10 production, IL-10
levels were measured in plasma samples of neonatal and adult mice at 24
and 48 h after challenge with an LD90. These
doses corresponded to 5 x 101 and 1 x
108 CFU in the neonates and adults, respectively.
IL-10 was below the limit of detection in plasma samples from adult
animals at either 24 or 48 h after infection, while significant
(p < 0.05) elevations were detected in
neonates (256 ± 75 and 644 ± 158, respectively, at 24 and
48 h; not shown). Because IL-10 elevations were not detected in
the adults at 24 and 48 h using an LD90,
additional experiments were performed using 50 times the
LD90 (i.e., 2.5 x 103
and 5 x 109 for neonates and adults,
respectively). Under these conditions, IL-10 elevations were detected
in both groups, reaching peak values at 48 h and slowly declining
thereafter (Fig. 1
A). However,
IL-10 plasma levels were significantly higher in neonatal mice relative
to adults at all tested times after infection
(p < 0.05).
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B shows IL-10 plasma levels in pups or adults injected s.c.
with 65 mg/kg of heat-killed L. monocytogenes. Significant
IL-10 plasma elevations over the basal values were observed in both
groups at 4, 6, 8, and 10 h after challenge, peaking at 8 h
(Fig. 1B). Again, IL-10 levels were markedly higher in the
pups, relative to adult animals, at all tested times
(p < 0.05). These data indicated that the higher IL-10 levels observed in the neonates during infection were not secondary to a decreased ability to restrict bacterial growth, and to a consequent increase in bacterial burden, but rather reflected a propensity of the neonates to overproduce IL-10 in response to Listeria.
Effects of IL-10 blockade in neonatal listeriosis
Next, it was of interest to assess whether the increased IL-10
response of neonates had a role during infection. Therefore, the
effects of IL-10 blockade were compared in infected neonatal and adult
mice. Neonatal and adult mice were pretreated with neutralizing
anti-IL-10 mAb (60 mg/kg) at 2 h before challenge with an
LD90 of L. monocytogenes. In
preliminary experiments, it was found that this anti-IL-10 dose was
sufficient to completely abrogate plasma IL-10 elevations in neonates
during infection. In adult animals, IL-10 blockade resulted in
significantly decreased lethality at 5 to 8 days after challenge (Fig. 2). However, no differences in survival
were noted from day 9 to the end of the experiment (day 15), indicating
that anti-IL-10 did not afford permanent protection. The effects of
IL-10 blockade were markedly different in neonates. In these,
pronounced protective effects were observed both early and late during
infection (Fig. 2). Alterations in lethality paralleled, in general,
changes in bacterial counts in the liver and the spleen (Fig. 3). However, CFU values fell in both
groups at 10 days, a time point at which lethality remained high. This
decrease in bacterial burden is more apparent than real, because the
low 10-day CFU values actually refer to the few mice that were
surviving.
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Cell types responsible for increased IL-10 production
Several cell types, including B and T lymphocytes and macrophages,
are capable of producing IL-10. Therefore, it was of interest to
identify the cell type predominantly responsible for increased neonatal
IL-10 responses. To this end, spleen cells were separated by glass
adherence in two populations. Equal numbers of unseparated cells, as
well as adherent and nonadherent cells, were incubated for 24 h
with heat-killed L. monocytogenes (50 µg/ml) and IL-10 was
measured in the supernatants. Fig. 4
shows that 3–5-fold higher IL-10 levels were detected in neonatal,
relative to adult, cultures using either unseparated or adherent cells.
In contrast, nonadherent cells showed moderate IL-10 production, which
did not differ between adults and neonates. These data indicated that:
1) in vivo differences in IL-10 production could be reproduced in vitro
using spleen cell cultures; 2) neonatal adherent cells produce higher
amounts of IL-10, relative to those of adults, in response to
Listeria; 3) adherent cells are the predominant cell type
responsible for IL-10 responses to killed L. monocytogenes,
in both adults and neonates. Although adherent cells were >90%
macrophages by esterase staining and phagocytosis (data not shown), our
data did not completely exclude that different cell types also
participated in IL-10 production. Indeed, increased numbers of
CD5+ (Ly-1) B lymphocytes, which are able to
produce IL-10 (34), are known to be present in the
neonatal period (35). Moreover, B lymphocytes, in addition
to macrophages, have been reported to produce IL-10 in response to
Listeria (36).
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Similar results were obtained using adherent cells depleted of
CD5+ lymphocytes (not shown). Therefore, in this
model, CD19+, CD45+, or
CD5+ cells were not apparently a major source of
IL-10 and were unlikely to account for the increased neonatal IL-10
production. In additional experiments, we sought to determine whether
the increased IL-10 response to L. monocytogenes was
specific for this pathogen or reflected a generic response of neonatal
macrophages to different types of stimuli. To this end, IL-10 levels
were measured after stimulating spleen cells with GBS, also a
Gram-positive neonatal pathogen, or with LPS, a classic means to induce
macrophage cytokine responses. Fig. 5
shows that neonatal cells responded with increased IL-10 production to
GBS or LPS, and that, therefore, different agents capable of
stimulating macrophages, in addition to Listeria, could
induce increased IL-10 responses in neonates.
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The differences between adults and neonates described above
indicated that there must be a transition from high to low level IL-10
production at some time during maturation of the defense system. To
determine when this transition occurred, mice of different age
were inoculated with 65 mg/kg of heat-killed Listeria, and
IL-10 levels measured in plasma samples at various times after
challenge. Fig. 6 shows that IL-10 levels
were 
10-fold higher in neonates relative to adults, confirming
previous studies reported in Fig. 1.
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also shows that pups reached low adult-like IL-10 levels only at
30 days of age. These data indicated that a markedly increased IL-10
production persisted throughout early life and that adult-like levels
are reached relatively late during development.
Increased IL-10 levels are not responsible for defective IFN-
production in neonates
In a previous study, we have demonstrated that early life is
associated, in mice, with a defective IFN- production and that high
level production is reached at 30 days after birth (11).
Since, in the present study, high level IL-10 responses were detected
in the same age groups that were previously found to have defective
IFN- production, we asked whether these phenomena were causally
related. To determine whether IL-10 blockade resulted in increased
IFN- production, neonatal or adult spleen cells were stimulated with
heat-killed L. monocytogenes in the presence of neutralizing
anti-IL-10 Abs (Genzyme) or normal rat IgG. Anti-IL-10 reduced by
>90% IL-10 levels in both neonatal or adult cultures (data not
shown). Both in the presence or in the absence of IL-10 blockade,
neonatal cultures did not produce increased IFN- levels following
stimulation with heat-killed Listeria (Fig. 7). In contrast, anti-IL-10
significantly increased IFN- production in adult cultures (Fig. 7).
These data indicated that increased neonatal IL-10 production could not
account for the inability of neonatal cells to produce
IFN- in vitro.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It was found in this study that, relative to adults, neonatal mice have markedly increased IL-10 plasma levels early in the course of infection. This difference was not secondary to inability to localize the infection or increased bacterial burden, because higher IL-10 responses were observed also in pups injected with heat-killed bacteria. Moreover, spleen cells from neonates produced higher IL-10 levels than those of adults, after in vitro stimulation with killed bacteria.
Previous studies using IL-10-deficient mice have clearly shown the detrimental effects of this cytokine in listeriosis (26). Therefore, it was of interest to determine whether the excess of IL-10 produced by the pups had biological consequences in terms of ability to restrict the infection. Our data showed marked beneficial effects of anti-IL-10 in the neonates, with moderate effects only in the adults. The latter finding is not in contrast with previous studies showing that IL-10-deficient adult mice are highly resistant to listeriosis (26). The incomplete protection we observed in anti-IL-10-treated adult mice may be related to incomplete neutralization of the cytokine in the microenvironment of the infection sites.
Differences in the time course of the infection in adults and neonates (i.e., transient vs prolonged, respectively) may also explain the long-term effects of IL-10 blockade observed in the pups, but not in the older animals. Nonetheless, the dramatic effects of anti-IL-10 in the neonates raise the possibility that increased production of the cytokine plays a role in the higher susceptibility of neonatal mice to listeriosis. Further studies investigating other factors, in addition to IL-10, will better clarify the relative contribution of IL-10 to increased neonatal susceptibility to these organisms.
Several mechanisms may account for the detrimental effects of endogenous IL-10 in neonatal listeriosis. IL-10 potently inhibits the microbicidal and Ag-presenting functions of macrophages (37, 38, 39). Interestingly, both of these functions are defective in the neonatal period. Macrophages derived from infant mice within 2 wk after birth are unable to kill intracellular Listeria (40). Moreover, neonatal macrophages show a reduced ability to present listerial Ags and a decreased expression of Ia molecules (41, 42). It will be of interest to determine whether IL-10 blockade can restore the microbicidal and Ag-presenting functions of neonatal macrophages.
In the present study, adherent macrophages were predominantly responsible for IL-10 production by spleen cells in response to killed bacteria. These data are in agreement with the ability of B and T cell-deficient RAG-1 (43) and SCID (44) mice to produce IL-10 in response to Listeria, but do not exclude the participation of other cell types, including B cells and T cells, which were also previously found to respond to Listeria (36). Indeed, in the present study, moderate, but significant IL-10 production was detected in the nonadherent cell populations of both adults and neonates. CD5+ B cells, which are capable of producing IL-10 and are present in increased numbers in neonatal spleen (34, 35), were not apparently the primary source of IL-10, because removal of these cells using specific Abs and C did not abrogate increased neonatal IL-10 responses.
Increased IL-10 responses were not confined to Listeria, but were also observed using LPS or GBS as stimuli. In contrast, recent studies indicate that human mononuclear cells from cord blood produce lower IL-10 levels in response to LPS, relative to adult cells (45, 46, 47). Differences between these studies and the present one may relate to differences between peripheral blood cells and tissue macrophages. Indeed, in the present study, overproduction of IL-10 in response to Listeria or LPS was observed both in vitro and in vivo. Studies are underway using isolated human monocytes to investigate age-related differences in IL-10 responses to different Gram-positive and Gram-negative bacterial components.
Why should neonatal macrophages overproduce IL-10 with potential detrimental effects on host responses to intracellular pathogens? No clear-cut answers are presently available. However, overproduction of IL-10 may start well before the neonatal period. Fetoplacental tissues spontaneously produce IL-10 and other factors capable of suppressing the production of type 1 cytokines (48). Evidence is accumulating that production of IL-10 during pregnancy has a role in preventing the aggression of fetal tissues by proinflammatory cytokines produced by maternal NK and CD8+ cells (49, 50). It is therefore possible that neonatal macrophages overproduce IL-10 because they are still under the influence of pregnancy-associated factors.
Irrespectively of their nature, these influences must be long lasting, because overproduction of IL-10 persists well beyond birth until early adulthood, as shown in this study. It is tempting to speculate that high level IL-10 production has a role not only in preventing fetal resorption, but also in controlling the regulated development of the immune system during early life. Indeed, IL-10 plays a central role in the homeostatic balance of proinflammatory and anti-inflammatory cytokines. The absence of IL-10 harms the host, as shown by observations that IL-10-deficient mice develop severe chronic enterocolitis (51). In addition, these mice die with strongly elevated TNF, IFN, and IL-12 blood levels after infection with Toxoplasma gondii (52) or Trypanosoma cruzii (26). In contrast, as mentioned above, IL-10-deficient mice show increased innate and acquired resistance to Listeria. Therefore, neonatal overproduction of IL-10 may be detrimental during listeriosis and irrelevant or beneficial in infection by other frequent neonatal pathogens, including T. gondii and GBS (52, 53).
In conclusion, we have shown in this study that neonatal mice produce high IL-10 levels during listeriosis or after the injection of killed bacteria or LPS. Overproduction of the cytokine is apparently detrimental during listeriosis, but may be beneficial in infections by other pathogens.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Giuseppe Teti, Istituto di Microbiologia, Torre Biologica (IIp.) Policlinico Universitario, Via Consolare Valeria 1, 98125 Messina, Italy. E-mail address:
3 Abbreviation used in this paper: GBS, group B streptococcal.
Received for publication June 15, 1998. Accepted for publication June 25, 1999.
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