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Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanism and Control, and
First Department of Surgery, Nagoya University School of Medicine, Nagoya, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. However, the effects of such reagents on host
defense against bacterial infection remain unknown. We show here that
in vivo administration of PGE2 significantly protected mice
against liver injury after Escherichia coli infection
but hampered the resolution of the infection. PGE2
significantly suppressed circulating TNF- and IL-12 levels but
increased the IL-10 production after E. coli challenge.
PGE2 inhibited the emergence of 
T cells in the
peritoneal cavity, which are important for host defense against
E. coli, and deteriorated bacterial exclusion in the
peritoneal cavity after E. coli
challenge. These results suggested that PGE2 affects host
defense mechanisms against E. coli
infection through modulation of cytokine production and T cell
accumulation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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are
secreted by phagocytes in response to infection (1, 2, 3). The combined
local effects of these cytokines result in an inflammatory response,
which is usually one of the immediate local reactions to infection.
IL-12 in synergy with TNF- can elicit production of large amounts of
IFN- by NK cells and T cells; this secreted IFN- is
crucial in controlling infections before CD4 Th1 cells can be activated
to produce cytokine (3). However, excessive inflammation responses
sometimes induce tissue damage. Indeed, massive TNF- release from
macrophages plays a central role in endotoxin-induced liver injury
(4, 5, 6). TNF- causes intravascular coagulation and thereby ischemia
of the organs, resulting in massive necrosis of the liver (6). TNF-
is also known to induce apoptosis of hepatocytes directly (7). IFN-
produced by NK cells and T cells potentiates the TNF- induced
apoptosis in liver (8). Hence, it has been shown that IL-12 plays
important roles in LPS-induced liver injury via stimulation of IFN-
producing cells (9).
A number of regulatory cytokines such as IL-4, IL-10, and TGF-ß are
described as having the capacity to block macrophage functions,
including TNF- release (10, 11, 12). These cytokines are termed
"macrophage-deactivating cytokines." Exogenous IL-10 protects mice
from septic shock and LPS-induced liver injury; conversely,
anti-IL-10 mAb treated mice exhibit an increased susceptibility to
LPS, suggesting that IL-10 plays a protective role in endotoxic shock
though the inhibition of excessive TNF- production (13, 14, 15). Thus,
excessive inflammatory responses are regulated by the
macrophage-deactivating cytokines such as IL-10.
Several cytokines involved in LPS-induced liver injury, such as
TNF-, IL-10, IL-12, IFN-, and IL-1ß, are reported to be
regulated by a cAMP-dependent signaling pathway (16, 17, 18, 19, 20, 21). Elevated
levels of cAMP are known to inhibit activation of nuclear factor
(NF-
B) via retarded degradation of inhibitory factor-B (IF-B),
while they stimulate activating transcription
factor/cAMP response element
(ATF/CRE)3 site-mediated gene transcription (22, 23, 24, 25).
Production of TNF- and IL-12 is inhibited by cAMP elevating agents,
since their genes contain an NF-B site in the 5' regulatory region,
whereas IL-10 is up-regulated by the cAMP-dependent pathway, since the
IL-10 gene contains a CRE/ATF-1-like site but no NF-B site in the 5'
regulatory region (19, 24, 26). PGE2, which activates
membrane adenylate cyclase, has been demonstrated to elevate
intracellular cAMP and consequently to activate cAMP-dependent protein
kinase, resulting in down-regulation of LPS-induced TNF- production
at the transcriptional and/or translational level (27, 28, 29, 30, 31). It has been
demonstrated that PGE2 increases LPS-induced IL-10
production by peritoneal macrophages (28) and inhibits IL-12 production
in an IL-10-independent manner (26). These findings suggest that
PGE2 can be used as an anti-inflammatory agent in
patients with fulminant and subfulminant viral hepatitis
(32, 33, 34, 35, 36, 37). However, inflammatory cytokines are important for control of
infection with various pathogens. Therefore, it would be of interest to
know whether PGE2 affects the host defense against
microbial infection.
In the present study, we focused on the effect of PGE2 on
host defense against infection with Escherichia coli, a
Gram-negative bacterium, the cell wall components of which contain LPS.
Our results demonstrated that PGE2 significantly suppressed
circulating TNF- and IL-12 and reversely increased IL-10,
consequently protecting against liver injury following E.
coli infection. However, PGE2 deteriorated the
host defense mechanism against E. coli infection accompanied
by inhibition of the emergence of T cells. The implications of
these findings for the mechanisms whereby PGE2 affects host
defense against E. coli infection were discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C3H/HeN mice were purchased from Japan SLC (Shizuoka, Japan). These mice were bred in our institute under specific pathogen-free conditions. Eight- to ten-week-old female mice were used for the experiments. E. coli (American Type Culture Collection No. 26; Manassas, VA) grown in brain-heart infusion broth (Difco Laboratories, Detroit, MI), was washed repeatedly, resuspended in PBS, and stored at -80°C in small aliquots until use. The concentration of bacteria was quantitated by plate counts.
Abs and reagents
Biotin-conjugated anti-CD3
mAb, FITC-conjugated
anti-TCRß mAb, and phycoerythrin (PE)-conjugated
anti-TCR mAb were purchased from PharMingen (San Diego, CA).
Red-613-conjugated streptavidin was purchased from Life Technologies
(Gaithersburg, MD). Prostaglandin E2-ß-cyclodextrin
(PGE2) and ß-cyclodextrin (ß-CD) were provided by Ono
Chemical (Osaka, Japan). PGE2 includes 7.69% prostaglandin
E2. mAbs against murine anti-TCR mAb (UC7-13D5)
were kindly provided by Dr. J. A. Bluestone (University of
Chicago, Chicago, IL). Isotype control Ab was hamster
anti-2,4,6-trinitrophenyl mAb, which were obtained by growing
hybridoma cells in serum-free medium (medium 101; Nissui
Pharmaceutical, Tokyo, Japan) and collecting the supernatant. Abs were
then concentrated and purified by 50% ammonium sulfate precipitation.
The purity of the preparation was confirmed by SDS-PAGE, and the
concentration of Ab was determined by the Lowry method. The mAbs,
diluted to 1 mg/ml in PBS, were stored at -70°C until used. Two
hundred micrograms of mAb in 500 µl was injected into the peritoneal
cavity on day 3 before primary infection with E. coli. In
the control group, 200 µg of control Ab was injected.
Treatment of mice
Mice were injected with PGE2 dissolved in ethanol
(2.6 mg/mouse in 500 ml) or with the same dose of ß-CD (as control)
dissolved in ethanol diluted in PBS (final ethanol concentration was
9%). Three hours after PGE2 or ß-CD challenge, mice were
inoculated with E. coli at a dose of 1.0 x
108 CFU/mouse (1/5 LD50) in 1.0 ml of PBS.
After being assessed for serum transaminase activity, mice were
inoculated with E. coli at a dose of 1.0 x
109 CFU/mouse (2x LD50). All injections
were performed via i.p. administration. Blood was obtained by a
retro-orbital plexus puncture at 3 and 8 h after E.
coli challenge, and serum levels of TNF-, IL-10, and IL-12 were
determined at these time points, respectively.
Assay for serum alanine aminotransaminase (ALT) activity
Liver injury was assayed by serum ALT activity. This activity
was determined using the serum transaminase test kit (DIA-Iatron,
Tokyo, Japan). Briefly, 40 µl of the serum sample was incubated with
200 µl of L-alanine and -ketoglutaric acid solution,
respectively, for 30 min at 37°C for ALT. Twenty minutes after the
addition of 200 ml of 2,4-dinitrophenylhydrazine, 2 ml of 0.4 N NaOH
was added and by UV absorption measured at 505 nm. ALT activities
(international units per liter) were calculated from the standard
curve.
Bacterial growth in organs
Three days after infection, peritoneal exudates were obtained from the peritoneal cavity by lavage with 3 ml of HBSS and serially diluted with HBSS. Serial dilutions of the exudate samples were plated to determine the viable number. For enumeration of viable counts in the liver, the liver was perfused with 8 ml of sterile HBSS to wash out bacteria in the blood vessels immediately after mice were bled. Livers and spleen were removed and separated into sterile Teflon-coated homogenizers containing 5 ml of cold PBS. After each organ was homogenized thoroughly, the homogenates were established by plating serial 10-fold dilutions in sterile distilled water on tryptic soy agar (Nissui Laboratories). Colonies were counted 24 h later, after incubation at 37°C.
Histologic studies
Livers were removed from control or PGE2-treated mice at 8 h after infection with E. coli. The livers were fixed with 10% buffered formalin, paraffin embedded, and stained with hematoxylin and eosin for light microscopic examination.
Peritoneal exudate cells (PEC)
Mice were i.p. infected with E. coli at a dose of 1/5 LD50 (1.0 x 108 CFU/mouse) in 1.0 ml of PBS on day 0. PEC were harvested 3 days after inoculation by peritoneal lavage with HBSS. The cells were collected by centrifugation at 110 x g for 5 min, washed twice, and resuspended at optimal concentration in RPMI 1640 medium (Life Technologies, Grand Island, NY) supplemented with 10% serum. PEC were spread on plastic plates at a concentration of 5 x 105 cells/ml, and incubated for 1 h in a CO2 incubator at 37°C to obtain nonadherent cells.
Flow cytometry analysis
For three-color analysis, plastic-nonadherent cells of PEC were incubated with saturating amounts of biotin-conjugated Ab for 30 min at 4°C. Cells were washed twice and incubated with FITC-, PE-, and Red-613-conjugated Abs for 30 min. Cells were analyzed with a FACScan flow cytometer (Becton Dickinson, San Jose, CA). We carefully gated cells by forward and side light scattering for the live lymphocytes. The data were analyzed with FACScan research software (Becton Dickinson).
Cytokine assays
TNF-, IL-10, and IL-12 levels in serum were determined by
ELISA. ELISAs for TNF- and IL-10 were performed in triplicate using
PharMingen mAbs according to the manufacturer’s instructions.
ELISA for IL-12 was performed using Genzyme mAb according to the
manufacturer’s instructions (Genzyme, Cambridge, MA).
Proliferation and IFN- assay
T cells were purified by cell sorting (using an EPICS
Elite (Coulter, Hialeah, FL) electric cell sorter) from the nonadherent
PEC on day 3 after E. coli infection. The purity of sorted
cells was >97%. Tissue culture 96-well plates were incubated
overnight at 4°C with 100 mg/ml anti-TCR mAb (UC7-13D5).
The plates were then washed thoroughly and incubated for 1 h at
37°C with RPMI 1640 medium containing 10% FCS. The sorted T cells
(3 x 104/well) were incubated in the
anti-TCR mAb-coated plates in the presence of murine rIL-12
(Genzyme). During the last 8 h of incubation, 1.0 µCi of
[3H]thymidine incorporation was determined by
scintillation counting. IFN- and IL-4 levels in the culture
supernatants were determined by ELISA (Genzyme).
Statistical analysis
Data were analyzed by Student’s t test, and a Bonferroni correction was applied for multiple comparison. The value of p < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cAMP-increasing agents are known to protect against LPS-induced
liver injury (15, 34, 35, 36, 37). We first examined whether administration of
PGE2 protects liver against liver injury following
infection with a high dose of E. coli. A lethal dose of
E. coli (1 x 109 CFU/mouse) was injected
i.p. into mice 3 h after an i.p. injection of 130 mg/kg of
PGE2 or ß-CD. As shown in Figure 1
, liver injury was induced after
E. coli infection, as assessed by serum ATL activities.
PGE2 treatment provided significant protection against
E. coli-induced liver injury compared with control ß-CD
(p < 0.05). The 130 mg/kg of PGE2
was an optimal dose for protection against the liver injury; the
maximal effect was obtained when PGE2 was given 3 h
before E. coli challenge.
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).
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We next examined bacterial growth to determine whether or not in
vivo administration of PGE2 was protective against
infection with E. coli. A 1/5 x LD50 dose
(1 x 108 CFU/mouse) of E. coli was
inoculated i.p. in mice 3 h after an i.p. injection of 130 mg/kg
of PGE2 or the same amount of ß-CD, and bacterial growth
in the peritoneal cavity, liver, and spleen were examined 3 days later.
As shown in Figure 3, the
PGE2 treatment exaggerated the bacteria growth following
E. coli challenge. This result suggests that exogenous
PGE2 reduces host defense against E. coli
infection.
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, IL-12, and IL-10
level after E. coli challenge
PGE2 is reported to inhibit TNF- and IL-12
production but enhance IL-10 synthesis by macrophages in response to
LPS stimulation (16, 26, 28). Therefore, the in vivo effect of
PGE2 on cytokine production was examined in the serum of
mice after E. coli infection. As shown in Figure 4, serum TNF- and IL-12 levels were
maximal in control mice 3 h after E. coli infection,
while these levels were significantly suppressed by in vivo
administration of PGE2 (p < 0.05).
On the other hand, levels of IL-10 were increased only marginally in
control mice after E. coli infection, but PGE2
treatment significantly enhanced IL-10 release after E. coli
challenge.
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T cells in
the peritoneal cavity after E. coli infection
A prominent increase in T cells was observed in the
peritoneal cavity after an i.p. infection with E. coli in
C3H/He mice (38). We examined the effect of PGE2 on the
influx of T cells in the peritoneal cavity after E.
coli inoculation. There was no difference in the numbers of
polymorphonuclear cells, lymphocytes, and macrophages in the peritoneal
cavity on day 3 after E. coli infection between mice
pretreated with or without PGE2 (data not shown). Flow
cytometry analyses of the expression of TCRß, TCR, and
CD3 were conducted on the plastic-nonadherent PEC on day 3 after
inoculation (Fig. 5A). A
representative result from five mice for expression of TCRß and
is shown in Figure 5A, after gating of
CD3+ T cells. Consistent with previous findings (34), the
percentage of T cells increased markedly to 82.0 ± 3.5%
in CD3+ T cells from <5% before E. coli
challenge in control mice, whereas it increased only to 39.2 ±
2.9% in PGE2-treated mice. Absolute numbers of T
cells in the peritoneal cavity were significantly less in
PGE2-treated mice than in control mice (Fig. 5B,
p < 0.05). Thus, PGE2 severely inhibits
the emergence of T cells in the peritoneal cavity after E.
coli infection. Although a dominant T cell response to
E. coli infection was observed, the protective role of the
T cells in E. coli infection remains to be
elucidated. To this end, we first examined cytokine production by
T cells in the presence of IL-12, which is known to induce
IFN- production by both resting and activated NK and T cells (3). As
shown in Figure 6, IFN- production was
only marginal when the T cells were cultured on the anti-TCR
mAb-coated plates without IL-12, while IL-12 induced
considerable IFN- production by the T cells. IL-4 production
was not detected in the culture of the T cells. To obtain direct
evidence for a protective role of T cells in E. coli
infection, we examined bacterial resolution in mice depleted of
T cells by treatment with anti-TCR mAb. T cells were
confirmed to be almost completely depleted in the peritoneal cavity 3
days after infection with 1 x 108 E. coli
bacteria in mice pretreated with 200 µg of anti-TCR mAb.
(Fig. 7A). As shown in Figure 7B, a significant increase in the number of E.
coli bacteria was evident in the peritoneal cavity and liver of
anti-TCR mAb-treated mice compared with control mAb-treated
mice. These results indicate that the T cells are important for
protection against E. coli infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-12, IL-1ß, and IL-10 (16, 17, 18, 19, 20, 21). Our
results show that administration of PGE2 decreased TNF-
and IL-12 production but enhanced IL-10 release in the serum following
E. coli challenge. An NF-B site is missing in the 5'
regulatory region of the IL-10 gene, whereas TNF- and IL-12 genes
contain such a site (19, 24, 26). PGE2 may directly
down-modulate TNF- and IL-12 production by inhibition of NF-B
activation and up-regulate IL-10 production through stimulation of
CRE/ATF-mediated gene transcription. IL-12 is known to be a potent
stimulator of IFN- production by NK and T cells (3), whereas IL-10
shuts down IFN- synthesis by these cells (10). Thus, it appears that
aberrant cytokine production by PGE2 administration affects
the mutual regulation of TNF-, IL-12, and IL-10 in their synthesis
after E. coli infection.
A protective effect of TNF- administration or a lethal effect of
depletion of TNF- or TNFR by Ab treatment or gene mutation has been
observed in mice infected with Listeria monocytogenes,
Salmonella, or endogenous bacteria (2, 39, 40, 41, 42). Thus,
TNF- is produced by macrophages in response to several Gram-positive
and -negative bacteria and is important for protection against
bacterial infection. IL-12 is also produced by macrophages stimulated
with such bacteria and exerts various biologic effects, including
enhanced proliferation and cytolytic activity of NK and Th1 cells as
well as induction of IFN-, which are important for host defense
against the infection (3). On the other hand, IL-10, which is produced
by macrophages and T cells, is a potent inhibitor of macrophage-derived
inflammatory cytokine synthesis (10). Since the balance of these
cytokines released by macrophages is important to the induction of host
defense, modulation of TNF-, IL-12, and IL-10 release from infected
macrophages is mainly responsible for the impaired host defense against
E. coli infection induced by PGE2
administration.
TNF- plays a pivotal role not only in host defense but also in the
pathogenesis of liver failure, which is caused by endotoxin/LPS derived
from Gram-negative bacteria (2, 6). IL-12 is also reported to be
involved in LPS-induced liver injury, presumably by activation of NK
and T cells capable of IFN- production and Fas-mediated cytotoxicity
(9). PGE2 severely suppressed the level of circulating
IL-12, in addition to TNF-, following E. coli
challenge. The suppression of both IL-12 and TNF- may be a mechanism
whereby PGE2 inhibits liver injury. Exogenous IL-10
effectively protects mice from lethal endotoxemia (13, 14). There is
evidence for the involvement of IL-10 in the differential deactivation
of murine peritoneal macrophages by PGE2 (43, 44). We have
also reported that a cAMP-increasing agent, dbcAMP, not only decreases
circulating TNF- but also increases circulating IL-10 after LPS
challenge in Propionibacterium acnes-treated mice and
consequently protect these mice from LPS-induced liver injury (15, 21).
Anti-IL-10 mAb treatment abrogated the protective effect of dbcAMP on
the LPS-induced liver injury in P. acnes-treated mice,
indicating a direct contribution of IL-10 to the protective effect of
dbcAMP on LPS-induced liver injury. Therefore, a mechanism of autocrine
feedback by increased IL-10 production may be involved in the
suppression by PGE2 in liver injury and host defense
following E. coli infection. PGE2 is
endogenously induced in several models of LPS or bacteria-induced
endotoxin shock (35, 36, 37). It would be interesting to determine whether
endogenous PGE2 induced in E. coli infection
regulates cytokine production and inflammation. In our preliminary
experiments, indomethacin, an inhibitor of cyclooxygenase, inhibited
PGE2 production and enhanced liver damage, accompanied by
increased TNF- and IL-12 production after E. coli
infection. It can be speculated that endogenous PGE2 is
meticulously regulated to obtain the "optimal" balance between
fulminant liver injury and overwhelming bacterial growth after
infection.
Dominant TCR T cell response to infections with various microbial
pathogens suggests that a significant fraction of T cells
represents a first line of host defense against infections with diverse
pathogens in nature (45, 46, 47, 48, 49, 50, 51). Takada et al. have reported prominent
increases in T cells in the peritoneal cavity of particular
strains including C3H/He after E. coli infection (38).
However, the roles of the T cells in E. coli
infection remain to be determined. Using mice depleted of T
cells by treatment with anti-TCR mAb or by C gene
targeting, T cells are shown to contribute to host defense
against infection with some parasites including Mycobacterium
tuberculosis, L. monocytogenes,
Plasmodium falciparum, and herpes simplex virus
(51, 52, 53, 54). Similarly, with mice depleted of T cells, we show here
a protective role for T cells in E. coli infection.
Furthermore, the emergence of T cells after E.
coli infection was suppressed, albeit partially, by
PGE2 administration, and bacterial growth was exaggerated
in these mice. IL-12 is a major inducer of differentiation of Th1 cells
producing IFN-, IL-2, and TNF-ß, while suppressing the development
of Th2 cells secreting IL-4 and IL-5 (3). Our results reveal that the
T cells appearing during E. coli infection were
mainly Th1-type cells, which were stimulated to produce IFN- in the
presence of IL-12 (47, 50). IL-12 was shown to activate T
cells to produce IFN- in synergy with TNF- (55). On the other
hand, IL-10 inhibit Th1 development by shutting down IFN- synthesis
(10). Therefore, we speculate that suppression of IL-12 and TNF- is
responsible for the impaired accumulation of T cells in
E. coli-infected mice. An increase in
intracellular cAMP levels up-regulates type 2 cytokines, and Th2-type
cell lines maintain higher levels of cAMP per cell than do Th1-type
cell lines (18, 56, 57, 58). PGE2 not only affects the balance
of TNF- and IL-10 in macrophages, but also affects Th1-type
cytokines such as IFN- and Th2-type cytokines such as IL-4 (56, 57, 58). Therefore, it is also possible that T cells appearing in
the peritoneal cavity after E. coli infection are skewed to
Th2-type cells producing IL-4 and that the Th1 response of the T
cells is suppressed. Additional experiments are required to
clarify this possibility.
In conclusion, PGE2 affects not only liver injury but also the host defense mechanism during E. coli infection through modulating inflammatory and anti-inflammatory cytokine production.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yasunobu Yoshikai, Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, 65 Tsurumai-cho Showa-ku Nagoya 466, Japan. E-mail address:
3 Abbreviations used in this paper: ATF, activating transcription factor; CRE, cAMP response element; ALT, alanine aminotransaminase; ß-CD, ß-cyclodextrin; dbcAMP, dibutyryl cAMP; PGE2, prostaglandin E2-ß-cyclodextrin; PE, phycoerythrin; PEC, peritoneal exudate cells.
Received for publication December 22, 1997. Accepted for publication May 11, 1998.
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