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,
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Departments of
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Surgery,
Experimental Internal Medicine,
Infectious Diseases, Tropical Medicine and AIDS, and
Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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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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35% (4), abdominal sepsis is associated with mortality
rates up to 80% (5). Although different bacteria have
been identified as causative organisms in peritonitis,
Escherichia coli remains one of the most common pathogens
(up to 60%) in intraperitoneal infections (6, 7).
Surgical and supportive treatment of peritonitis often do not suffice,
and an increase in resistance to many antibiotic compounds has
developed (8, 9), especially among the
Enterobacteriaceae, where some isolates have acquired
extended spectrum 
-lactamases (10, 11). More knowledge
of the regulation of inflammatory responses during peritonitis is
warranted. Cytokines play an important role in the pathogenesis of bacterial infections (12). In models of severe systemic infection or inflammation produced by i.v. administration of high doses of bacteria or bacterial products such as endotoxin, excessive production of proinflammatory cytokines significantly contributes to organ failure and death, as reflected by findings that neutralization of either TNF or IL-1 activity markedly reduced mortality in these systemic challenge models (13, 14, 15). However, in experiments in which an at least initially localized infection was induced, including pneumonia and peritonitis, the local activity of proinflammatory cytokines appeared important for antibacterial host defense at the site of the infection (16, 17, 18, 19). Together these data suggest that proinflammatory cytokines function as "double-edged swords," on the one hand required locally for effective antibacterial effector mechanisms, in contrast potentially toxic when secreted into the circulation.
IL-10 is an 18-kDa cytokine produced under different conditions of immune activation by a variety of cell types, including T cells, B cells, monocytes, and macrophages (20, 21). IL-10 is considered a prototypic anti-inflammatory cytokine and potently inhibits the production of proinflammatory cytokines in vitro and in vivo (22, 23, 24, 25, 26). Several animal studies have pointed to an important role of IL-10 in the pathogenesis of bacterial infection. Elevated plasma concentrations of IL-10 have been found in patients with sepsis (27, 28). In mouse models of systemic inflammation induced by injection of endotoxin, IL-10 serves a protective role. Indeed, elimination of endogenous IL-10 resulted in an increased production of several proinflammatory cytokines, including TNF, and an enhanced mortality (29, 30). Similarly, IL-10 gene-deficient (IL-10-/-) mice demonstrated an enhanced mortality after endotoxin injection, which was associated with elevated levels of TNF and several other proinflammatory mediators (31). The role of endogenous IL-10 in localized bacterial infection is less unequivocal. During murine pneumonia, IL-10 produced within the pulmonary compartment impaired host defense against invading bacteria, as reflected by findings that treatment with anti-IL-10 Abs inhibited bacterial outgrowth in lungs and improved survival (32, 33). However, during septic peritonitis induced by cecal ligation and puncture (CLP) elimination of IL-10 was associated with an increased mortality (34, 35). The mechanisms by which anti-IL-10 treatment increased mortality during peritonitis were not elucidated in these previous studies. In particular, no attempts were undertaken to determine the effect of IL-10 on bacterial clearance from the peritoneal cavity and on the development of a systemic inflammatory response syndrome. Therefore, in this study we sought to determine the influence of endogenous IL-10 on host defense mechanisms during E. coli peritonitis, making use of IL-10-/- mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 wild-type (IL-10+/+) mice were purchased from Harlan CPB (Zeist, The Netherlands). C57BL/6 IL-10-/- mice were purchased from The Jackson Laboratory (Bar Harbor, ME). All mice were housed (five per cage) in the same temperature-controlled room with alternating 12-h light/dark cycles, and were allowed to equilibrate for at least 5 days before the study. Animals were provided regular mice chow (SRM-A; Hope Farms, Woerden, The Netherlands) and water ad libitum. Age- (8–10 wk) and sex-matched IL-10+/+ and IL-10-/- mice were used in all experiments. The experiments were approved by the Institutional Animal Care and Use Committee of the Academic Medical Center, Amsterdam, The Netherlands.
Antibodies
Rat anti-mouse TNF neutralizing mAb was provided by David Shealy (Centocor, Malvern, PA). Rat IgG2a (clone R7D4) was used as control Ab. Abs were given i.p. in a dose of 0.5 mg 2 h before induction of peritonitis.
Induction of peritonitis
E. coli O18:K1 was cultured in Luria Bertani medium (LB; Difco, Detroit, MI) at 37°C, harvested at mid-log phase, and washed twice with sterile saline before injection to clear the bacteria of medium. Mice were injected i.p. with 102, 103, or 104 viable E. coli O18:K1 CFU in 200 µl sterile isotonic saline. The inoculum was plated immediately after inoculation on blood agar plates to determine viable counts. Control mice received 200 µl normal saline.
Monitoring of mortality and organ and blood sampling
In survival studies, mortality was assessed every 12 h during the first 4 days after E. coli challenge. In preliminary studies, mortality occurred predominantly between 24 and 36 h after E. coli challenge; therefore, mortality was assessed every hour in this period. Mice that survived >3 days appeared to be permanent survivors.
At time of sacrifice, mice were first anesthetized by inhalation of isoflurane (Abbott Laboratories, Kent, U.K.)/O2 (2%/2 liters). A peritoneal lavage was then performed with 3 ml sterile isotonic saline using an 18-gauge needle, and peritoneal lavage fluid was collected in sterile tubes (Plastipack; BD Biosciences, Mountain View, CA). The recovery of peritoneal fluid was >90% in each experiment and did not differ between groups. After collection of peritoneal fluid, deeper anesthesia was induced by i.p. injection of 0.07 ml/g FFM mixture (Fentanyl (0.315 mg/ml)-Fluanisone (10 mg/ml) (Janssen, Beersen, Belgium), Midazolam (5 mg/ml; Roche, Mijdrecht, The Netherlands). Next, the abdomen was opened and blood was drawn from the lower caval vein into a sterile syringe, transferred to tubes containing EDTA (K3) (15%), and immediately placed on ice. Blood was used for hemologic and chemical analyses and for measurement of cytokine levels. Plasma for these determinations was prepared by centrifugation at 3000 x g for 10 min at 4°C, after which aliquots were stored at -20°C.
Histologic analysis
Shortly after killing, samples from all liver lobes and other parenchymal organs were removed, fixed in 4% formalin, and embedded in paraffin for routine histology. Sections of 2–5 µm thickness were stained with hematoxylin and eosin. Histologic examination was performed on coded samples by two independent investigators, blinded for treatment groups.
Assays
Cytokines and chemokines were measured by ELISAs according to the recommendations of the manufacturer (with detection limits in pg/ml), i.e., TNF (31.2) (Genzyme, Cambridge, MA), IL-10 (24.7) (PharMingen, San Diego, CA), macrophage inflammatory protein-2 (MIP-2) (9.6), and keratinocyte (KC) (4) (both obtained from R&D Systems, Minneapolis, MN). Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), creatinine, and amylase were determined with commercially available kits (Sigma, St. Louis, MO), using a Hitachi analyzer (Boehringer Mannheim, Mannheim, Germany) according to the manufacturer’s instructions.
Enumeration of bacteria
Ten-fold serial dilutions of peritoneal fluid, whole blood, and lung homogenates were plated on blood agar plates and incubated at 37°C and 5% CO2. CFU were counted after 24 h. Lung homogenates were prepared by homogenization at 4°C in four volumes of sterile saline using a tissue homogenizer (Biospec Products, Bartlesville, OK).
Cell counts and differentials
Cell counts, determined in triplicate on each peritoneal fluid sample, were quantitated using a hemacytometer. Subsequently peritoneal fluid was centrifuged at 1400 x g for 10 min; the supernatant was collected in sterile tubes and stored at -20°C until determination of cytokines. The pellet was diluted with PBS until a final concentration of 105 cells/ml and differential cell counts were performed on cytospin preparations stained with a modified Giemsa stain (Diff-Quick; Dade Behring AG, Düdingen, Switzerland) according to the manufacturer’s instructions. Cell differentials were determined in duplicate by two independent investigators.
Statistical analysis
All values are given as means ± SE. Comparisons were done by unpaired Student’s t tests with Bonferroni correction where appropriate. Survival curves were compared with the log-rank test. Values of p < 0.05 were considered to represent a significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In normal wild-type mice, peritonitis was associated with elevated
IL-10 concentrations in both plasma and peritoneal fluid at 6 and
24 h after infection (Fig. 1
). IL-10
levels increased with increasing doses of E. coli, and at
each bacterial dose were 5-fold higher in peritoneal fluid than in
plasma. After inoculation with 102 CFU E.
coli, IL-10 levels in peritoneal fluid and plasma peaked at 6
h, whereas after infection with higher doses, 103
and 104 CFU E. coli, IL-10 levels
peaked after 24 h. Mice that were i.p. injected with sterile
saline did not have detectable IL-10 in peritoneal fluid or blood. In
addition, in IL-10-/- mice no IL-10
immunoreactivity could be measured at any time point.
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Having established that IL-10 is produced during peritonitis, we
wished to determine the role of endogenous IL-10 in antibacterial
defense. For this purpose bacterial outgrowth was determined at 6 and
24 h after induction of peritonitis by either
102, 103, or
104 CFU E. coli (Fig. 2). We counted CFU in three body
compartments: 1) the peritoneal cavity (the site of the infection), 2)
blood (to evaluate to which extent the infection became systemic), and
3) the lung (an organ distant from the primary site of infection). At
6 h after inoculation with any of the three doses, similar numbers
of CFU were recovered from IL-10+/+ and
IL-10-/- mice, except for peritoneal fluid
obtained from IL-10+/+ mice after infection with
103 CFU, which showed more CFU than peritoneal
fluid obtained from IL-10-/- mice inoculated
with this dose (p < 0.05). At 24 h after
infection with 102 or 103
CFU, from only some of the IL-10+/+ mice, but
none of the IL-10-/- mice, E. coli
could be recovered from peritoneal fluid, blood, and lungs
(p < 0.05 for lungs after both
102 and 103 CFU,
IL-10+/+ vs IL-10-/-;
p < 0.05 for peritoneal fluid after
103 CFU, IL-10+/+ vs
IL-10-/-). At 24 h after infection with
104 CFU, IL-10+/+ mice had
significantly more CFU in their peritoneal fluid, blood, and lungs than
IL-10-/- mice (all p <
0.05). Hence, overall outgrowth of E. coli was impaired in
IL-10-/- mice when compared with
IL-10+/+ mice in all body compartments tested.
Subsequent studies on host defense mechanisms during peritonitis in
IL-10-/- and IL-10+/+
mice were performed using a bacterial inoculum of
103 CFU.
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Because leukocytes play an important role in the local host
defense against invading bacteria, we next determined leukocyte counts
and differentials in peritoneal fluid during peritonitis.
Intraperitoneal administration of 103 CFU
E. coli resulted in an influx of leukocytes into the
peritoneal fluid, which was mainly associated with an increase in
neutrophil numbers and which was especially apparent at 6 h after
infection (Table I). At this early time
point, IL-10-/- mice had more neutrophils in
their peritoneal fluid than IL-10+/+ mice
(p < 0.05). Peritoneal fluid leukocyte numbers
decreased between 6 and 24 h postinfection in both mouse strains,
although the number of neutrophils recovered from peritoneal fluid of
IL-10-/- mice at 24 h remained higher
(p < 0.05).
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Because IL-10 has been found to inhibit TNF production in vitro
and in vivo (20, 21, 22, 23, 24, 25, 26), and because TNF is considered an
important proinflammatory mediator in bacterial infection
(12), we were interested in TNF release in peritoneal
fluid and plasma during peritonitis in IL-10+/+
and IL-10-/- mice. Peritonitis was associated
with an increase in TNF concentrations in both peritoneal fluid and
plasma (Fig. 3, upper panels).
IL-10-/- mice had higher TNF concentrations in
peritoneal fluid and plasma than IL-10+/+ mice
(p < 0.05).
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, lower panels). Intraperitoneal administration of
E. coli resulted in a rise in peritoneal fluid and plasma
MIP-2 and KC levels. IL-10-/- mice had higher
levels of MIP-2 and KC in peritoneal fluid and plasma than
IL-10+/+ mice (p <
0.05). IL-10-/- mice have more severe multiple organ damage
Abdominal sepsis can be associated with multiple organ failure
(37). To determine the role of endogenous IL-10 herein, we
measured biochemical parameters of liver damage (ASAT, ALAT), pancreas
damage (amylase), and renal failure (creatinine) at 24 h after
i.p. injection of 103 E. coli CFU
(Fig. 4).
IL-10-/- mice demonstrated biochemical evidence
of more severe multiple organ damage than
IL-10+/+ mice, as reflected by higher ALAT, ASAT,
amylase, and creatinine concentrations (all p <
0.05).
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). Vascular congestion was generalized
in all organs examined, and more obvious in
IL-10-/- mice compared with
IL-10+/+ mice. In the livers of
IL-10+/+ mice, thrombotic occlusion in portal
areas, enlargement of portal tracts by mononuclear cells, micro and
macrovacuolar steatosis, and scattered foci of hepatocellular
degeneration and necrosis were noted. These changes were more
pronounced in livers of IL-10-/- mice,
especially with respect to the extent of hepatocellular necrosis,
characterized by garland-shaped necrotic areas, covering almost
half of the liver parenchyma, whereas in
IL-10+/+ this was far less. When inspecting the
lungs macroscopically, the lungs of IL-10+/+ mice
were less hyperemic and showed fewer hemorrhagic spots compared with
IL-10-/- mice. In addition, lungs of both mouse
strains displayed macroscopic hemorrhage and generalized
endovasculitis. IL-10+/+ mice showed fewer
thrombotic lesions and inflammatory infiltrates in the alveolar septa
than IL-10-/- mice. Noteworthy,
IL-10+/+ mice suffered more often from bacterial
pleuritis with large purulent exudates. Increased levels of creatinine
were predominantly due to prerenal failure and general tissue
deterioration (e.g., muscle tissue) because there were only mild
inflammatory changes in the kidneys with sporadic necrotic tubular
cells.
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TNF is considered a central mediator in the early host response to
bacterial infection. On the one hand, high levels of TNF in the
circulation can cause severe tissue toxicity and organ damage
(38, 39). In contrast, at local tissue level, TNF
contributes to an effective host defense (16, 17, 18, 19). Because
IL-10-/- mice displayed elevated levels of TNF
in both peritoneal fluid and plasma (Fig. 3), we were interested to
determine the role of enhanced TNF release in the altered host
responses to peritonitis in IL-10-/- mice.
Therefore, we pretreated IL-10+/+ and
IL-10-/- mice with a neutralizing
anti-mouse TNF mAb or an irrelevant control mAb 2 h before
infection with 103 E. coli CFU and
determined bacterial outgrowth, leukocyte counts in peritoneal fluid,
and biochemical parameters of organ damage at 24 h after
inoculation. In these experiments, IL-10-/-
mice treated with the control mAb showed fewer E.
coli CFU in peritoneal fluid, blood, and lungs, an enhanced influx
of cells to the peritoneal cavity, and increased levels of biochemical
parameters of liver and pancreas damage and renal failure when compared
with IL-10+/+ mice treated with the control mAb
(Figs. 6 and 7, Table II), confirming the experiments presented
in Figs. 2 and 4, and Table I. Anti-TNF did not significantly
influence the number of E. coli CFUs recovered from
peritoneal fluid, blood, or lungs in either
IL-10+/+ or IL-10-/- mice
(Fig. 6). In addition, in IL-10+/+ mice
anti-TNF did not influence leukocyte recruitment to the peritoneal
cavity (Table II) or biochemical evidence of multiple organ damage
(Fig. 7). However, in IL-10-/- mice,
anti-TNF reduced inflammatory responses to E. coli
peritonitis, i.e., anti-TNF attenuated leukocyte influx and
especially neutrophil influx in peritoneal fluid
(p < 0.05 vs IL-10-/-
mice treated with control mAb; Table II), and diminished the rises in
ALAT, ASAT, amylase, and creatinine (all p < 0.05;
Fig. 7).
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To examine the role of endogenous IL-10 and TNF in lethality
induced by peritonitis, IL-10+/+ and
IL-10-/- mice were pretreated (2 h) with
either anti-TNF or control mAb, inoculated i.p. with
103 CFU E. coli, and followed for 10
days (Fig. 8). All deaths occurred
between days 1 and 3; mice surviving for 3 days appeared permanent
survivors. IL-10-/- mice treated with control
mAb died earlier and to a greater extent than
IL-10+/+ mice treated with control mAb (13/19 or
68% vs 6/18 or 33%, p < 0.05). This survival
disadvantage of IL-10-/- mice disappeared after
treatment with anti-TNF (mortality 7/18 or 39%, nonsignificant vs
IL-10+/+ mice treated with control mAb). Anti-TNF
tended to increase survival in IL-10+/+ mice
(nonsignificant).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The protective role of endogenous IL-10 in systemic inflammation induced by a bolus dose of endotoxin has been established in a number of investigations (29, 30, 31). However, in these studies the potential disadvantageous effects of IL-10 on the local outgrowth of bacteria in an infected organ and the subsequent dissemination of bacteria, resulting in sepsis, could not be examined. The role of IL-10 in localized bacterial infection seems to depend on the organ that is infected. Indeed, immunoneutralization of IL-10 in mouse models of Gram-negative or Gram-positive pneumonia was associated with an improved bacterial clearance from the lungs and an increased survival rate (32, 33). On the contrary, anti-IL-10 treatment of mice with peritonitis caused by CLP was associated with enhanced lethality (34, 35). Whether endogenous IL-10 influenced bacterial clearance from the peritoneal cavity or the development of multiple organ damage was not investigated in these previous studies. We now show that, similar to its effect in the pulmonary compartment, endogenous IL-10 impaired bacterial clearance from the peritoneal cavity during E. coli peritonitis, which was associated with dissemination of bacteria to other sites in the body. However, this did not result in an exaggerated systemic inflammatory response syndrome. Endogenous IL-10 was found to inhibit the local and systemic release of TNF, which at least in part appeared associated to the development of multiple organ damage and death. These data illustrate the importance of inflammation in lethality induced by abdominal bacterial infection, i.e., the inflammatory response induced by the bacteria, tightly controlled by endogenous IL-10, rather than the bacterial load itself, determined the outcome. It remains to be established why in pulmonary infection models elimination of IL-10 improved survival (32, 33). Conceivably, such pneumonia models are not associated with a systemic inflammatory response syndrome and multiple organ damage, an issue that was not investigated in these reports (32, 33). If this is true, the beneficial inhibitory effects of endogenous IL-10 on systemic inflammation would not play a significant role in the outcome of experimental pneumonia.
Treatment of normal wild-type mice with anti-TNF did not significantly influence the course of E. coli peritonitis. This finding is in line with previous studies that reported no effect of anti-TNF treatment on survival during peritonitis induced by i.p. administration of E. coli (41, 42) or CLP (34, 43). Our present study adds to these earlier reports that anti-TNF not only failed to influence survival, but also had no effect on bacterial clearance and the development of multiple organ damage. Together these data suggest that TNF likely does not play an important role in the pathogenesis of abdominal sepsis, although in mild sublethal peritonitis endogenous TNF may contribute to host defense (16). This study also indicates that during abdominal sepsis the anti-inflammatory arm of the cytokine network (i.e., IL-10) may have a more important regulatory role in the host response than the proinflammatory arm of the cytokine network (i.e., TNF). This supposition is supported by a recent study in which neutralization of another anti-inflammatory cytokine, IL-13, enhanced systemic inflammation and reduced survival during peritonitis induced by CLP (44). Anti-IL-13 therapy did not alter the bacterial load in the peritoneal cavity nor did it influence leukocyte influx or IL-10 levels, suggesting that IL-13 and IL-10 influence host defense during peritonitis by different mechanisms. Interestingly, anti-TNF did influence host responses during peritonitis in IL-10-/- mice. In particular, it diminished the development of multiple organ damage and it reduced mortality. Because anti-TNF did not affect bacterial clearance in IL-10-/- mice, these data further suggest that the systemic inflammatory response syndrome rather than the bacterial dissemination determined the outcome. In addition, whereas the wild-type TNF response did not have an important impact on the course of peritonitis, the exaggerated TNF response in IL-10-/- mice apparently did contribute to multiple organ damage and death. This observation is in line with studies in which sterile systemic inflammation was induced by bolus administration of endotoxin. Indeed, anti-TNF therapy partly reversed the increased susceptibility of anti-IL-10-treated and IL-10-/- mice to endotoxin-induced lethality (30, 31).
The mechanisms involved in the improved clearance of bacteria from the peritoneal cavity of IL-10-/- mice remain to be established. IL-10 may exert direct anti-inflammatory effects on cells involved in host defense against bacteria, i.e., IL-10 can decrease neutrophil degranulation and chemotaxis, and can suppress oxygen radical and NO synthesis (21). The net effect of the increased influx of neutrophils in peritoneal fluid of IL-10-/- mice, likely at least in part mediated by locally elevated concentrations of the CXC chemokines MIP-2 and KC (45, 46), is uncertain. On the one hand, this enhanced inflammatory response may have contributed to an effective local antibacterial defense (47). On the other hand, accumulation of neutrophils in the peritoneal cavity may also injure the host, as suggested by a report in which a reduction in neutrophil influx to the abdomen by treatment with an anti-MIP-2 Ab was associated with increased survival during peritonitis induced by CLP (45). In this respect, it should be noted that anti-TNF reduced neutrophil influx in peritoneal fluid of IL-10-/- mice without influencing bacterial clearance, suggesting that neutrophils did not play a major role in local antibacterial effector mechanisms. Moreover, considering the earlier findings in anti-MIP-2-treated mice (45), this anti-TNF effect may have contributed to the protective effect of this intervention.
It should be noted that IL-10 may influence host defense mechanisms during peritonitis in other ways than by diminishing TNF production. Indeed, although this study focused on possible interactions between IL-10 and TNF, it is conceivable that other proinflammatory mediators not measured and/or antagonized may have played a role in the phenotype of IL-10-/- mice during peritonitis. For example, IL-10 has been reported to inhibit the expression of adhesion molecules on endothelial cells and to attenuate certain proinflammatory neutrophil functions (48, 49, 50, 51).
During abdominal sepsis, proinflammatory and anti-inflammatory members of the cytokine network are considered to regulate local antibacterial effector mechanisms on the one hand, and the systemic inflammatory response syndrome ensuing from the severe bacterial infection on the other hand. If the balance in the cytokine network is lost, the inflammatory response to infection can become self-destructive. Here we demonstrate the seemingly paradoxical role of endogenous IL-10 during septic peritonitis. The absence of IL-10 was detrimental to the survival of mice, accompanied by profound multiple organ damage, despite a more effective bacterial clearance and a reduced dissemination of bacteria to distant organs. These data exemplify the complex role of IL-10 in bacterial infection, and indicate that the net effect of endogenous IL-10 on the outcome of a bacterial infection is determined by the balance between its local effects (facilitating the outgrowth of microorganisms) and its systemic effects (attenuating inflammation).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Tom van der Poll, Department of Experimental Internal Medicine, Suite G2-132, Academic Medical Center, Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
3 Abbreviations used in this paper: IL-10-/-, IL-10 gene deficient; IL-10+/+, C57BL/6 wild type; MIP-2, macrophage inflammatory protein; KC, keratinocyte; ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; CLP, cecal ligation and puncture.
Received for publication January 11, 2001. Accepted for publication March 8, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Circ. Shock 30:279.[Medline]
impairs host defense during pneumococcal pneumonia in mice. Am. J. Respir. Crit. Care Med. 155:603.[Abstract]
and tumor necrosis factor production during experimental endotoxemia. Eur. J. Immunol. 24:1167.[Medline]
in intravascular and peritonitis models of sepsis. J. Infect. Dis. 163:83.[Medline]
and to lipopolysaccharide. J. Immunol. 148:1890.[Abstract]
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 G. F. Debes, K. Bonhagen, T. Wolff, U. Kretschmer, S. Krautwald, T. Kamradt, and A. Hamann CC Chemokine Receptor 7 Expression by Effector/Memory CD4+ T Cells Depends on Antigen Specificity and Tissue Localization during Influenza A Virus Infection J. Virol., July 15, 2004; 78(14): 7528 - 7535. [Abstract] [Full Text] [PDF]
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S. Knapp, A. F. de Vos, S. Florquin, D. T. Golenbock, and T. van der Poll Lipopolysaccharide Binding Protein Is an Essential Component of the Innate Immune Response to Escherichia coli Peritonitis in Mice Infect. Immun., December 1, 2003; 71(12): 6747 - 6753. [Abstract] [Full Text] [PDF]
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A. Matsukawa, K. Takeda, S. Kudo, T. Maeda, M. Kagayama, and S. Akira Aberrant Inflammation and Lethality to Septic Peritonitis in Mice Lacking STAT3 in Macrophages and Neutrophils J. Immunol., December 1, 2003; 171(11): 6198 - 6205. [Abstract] [Full Text] [PDF]
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S. Weijer, M. E. Sewnath, A. F. de Vos, S. Florquin, K. van der Sluis, D. J. Gouma, K. Takeda, S. Akira, and T. van der Poll Interleukin-18 Facilitates the Early Antimicrobial Host Response to Escherichia coli Peritonitis Infect. Immun., October 1, 2003; 71(10): 5488 - 5497. [Abstract] [Full Text] [PDF]
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T. L. Ness, C. M. Hogaboam, R. M. Strieter, and S. L. Kunkel Immunomodulatory Role of CXCR2 During Experimental Septic Peritonitis J. Immunol., October 1, 2003; 171(7): 3775 - 3784. [Abstract] [Full Text] [PDF]
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S. C. Higgins, E. C. Lavelle, C. McCann, B. Keogh, E. McNeela, P. Byrne, B. O'Gorman, A. Jarnicki, P. McGuirk, and K. H. G. Mills Toll-Like Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology J. Immunol., September 15, 2003; 171(6): 3119 - 3127. [Abstract] [Full Text] [PDF]
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 M. Levi, J. Dorffler-Melly, P. Reitsma, H. Buller, S. Florquin, T. van der Poll, and P. Carmeliet Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice Blood, June 15, 2003; 101(12): 4823 - 4827. [Abstract] [Full Text] [PDF]
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N. Cole, M. Krockenberger, F. Stapleton, S. Khan, E. Hume, A. J. Husband, and M. Willcox Experimental Pseudomonas aeruginosa Keratitis in Interleukin-10 Gene Knockout Mice Infect. Immun., March 1, 2003; 71(3): 1328 - 1336. [Abstract] [Full Text] [PDF]
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J. Turner, M. Gonzalez-Juarrero, D. L. Ellis, R. J. Basaraba, A. Kipnis, I. M. Orme, and A. M. Cooper In Vivo IL-10 Production Reactivates Chronic Pulmonary Tuberculosis in C57BL/6 Mice J. Immunol., December 1, 2002; 169(11): 6343 - 6351. [Abstract] [Full Text] [PDF]
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H. W. Murray, C. M. Lu, S. Mauze, S. Freeman, A. L. Moreira, G. Kaplan, and R. L. Coffman Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy Infect. Immun., November 1, 2002; 70(11): 6284 - 6293. [Abstract] [Full Text] [PDF]
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S. Q. Latifi, M. A. O'Riordan, and A. D. Levine Interleukin-10 Controls the Onset of Irreversible Septic Shock Infect. Immun., August 1, 2002; 70(8): 4441 - 4446. [Abstract] [Full Text] [PDF]
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Y. Kalechman, U. Gafter, R. Gal, G. Rushkin, D. Yan, M. Albeck, and B. Sredni Anti-IL-10 Therapeutic Strategy Using the Immunomodulator AS101 in Protecting Mice from Sepsis-Induced Death: Dependence on Timing of Immunomodulating Intervention J. Immunol., July 1, 2002; 169(1): 384 - 392. [Abstract] [Full Text] [PDF]
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 T. K. Varma, C. Y. Lin, T. E. Toliver-Kinsky, and E. R. Sherwood Endotoxin-Induced Gamma Interferon Production: Contributing Cell Types and Key Regulatory Factors Clin. Vaccine Immunol., May 1, 2002; 9(3): 530 - 543. [Abstract] [Full Text] [PDF]
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