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Departments of
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Pathology and
Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were not
altered with anti-MCP-1 Abs. However, anti-MCP-1 Abs reduced
the peritoneal levels of leukotriene B4 (LTB4)
by 59%. The i.p. injection of MCP-1 into normal mice resulted in
elevated levels of LTB4 in the peritoneum. In vitro, MCP-1
stimulated the production of LTB4 from peritoneal
macrophages, in a dose-dependent manner. A specific LTB4
receptor antagonist (CP-105,696) inhibited CLP-induced recruitment of
both neutrophils and macrophages, which was accompanied by a reduced
level of MCP-1 in the peritoneum. Finally, administration of CP-105,696
was extremely detrimental to the survival of mice following CLP. These
experiments demonstrate that endogenous MCP-1 serves as an indirect
mediator to attract neutrophils via the production of LTB4,
and suggest the cross-talk can occur between MCP-1 and the lipid
mediator LTB4 during septic peritonitis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A growing body of evidence suggests that the recruitment of leukocytes
is governed by cell-specific chemoattractants, called chemokines
(7). Chemokines are mainly divided into two subfamilies.
CXC chemokines are typically chemotactic for neutrophils whereas CC
chemokines attract and activate mononuclear cells (7).
IL-8, a prototype of CXC chemokines, was detected in
peritoneal fluids of patients with septic peritonitis (8),
while macrophage inflammatory protein-2
(MIP-2)3 a murine CXC chemokine
functionally equivalent to human IL-8, was previously found in the
peritoneal fluids in a murine model of septic peritonitis
(9). These studies suggest a role of CXC chemokines in
both clinical and experimental septic peritonitis. Monocyte
chemoattractant protein (MCP)-1, a prototype of CC chemokines, is
produced by a variety of cells in vitro after stimulation with TNF-,
IL-1, or endotoxin (10), which are all involved in the
pathogenesis of sepsis (11). Elevated levels of MCP-1 have
been detected in plasma of patients with sepsis (12), as
well as after administration of endotoxin to experimental animals or
human volunteers (13, 14). Collectively, these
investigations have clearly demonstrated the presence of MCP-1 in
association with the development of septic peritonitis; however, the
mechanistic role of MCP-1 in sepsis evolving from peritonitis is
unclear.
In the present study, we have assessed the function of endogenous MCP-1 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). The pathology of this model results from a polymicrobial peritonitis due to the leakage of intestinal flora from the puncture wounds and mimics clinical sepsis with peritonitis associated with postsurgical or accidental trauma (15). Using this model, we have shown that MCP-1 can direct the host response to this pathogenic challenge via the establishment of novel in vivo inflammatory cascades. The contribution of this CC chemokine was first assessed via neutralization studies, where Abs directed against murine MCP-1 significantly increased the mortality rate due to the developing peritonitis. At the mechanistic level, MCP-1 was found to play an important role in the elicitation of both macrophages and neutrophils. While monocyte recruitment is a known biological activity of MCP-1, we have found that MCP-1 can attract neutrophils via the production of leukotriene B4 (LTB4) during the evolution of CLP. Our data also demonstrate that LTB4 can induce the production of MCP-1, suggesting that the inflammation due to CLP can be amplified by cross-talk between MCP-1 and LTB4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female CD-1 mice (6 to 8 wk of age) were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the animal care facility unit (University Laboratory of Animal Medicine). The animal use committee at the University of Michigan approved all studies. The total number of mice used in this study was 330.
CLP model
CLP surgeries were performed as described previously (9, 15). In brief, the mice were anesthetized with an i.p. injection of ketamine HCl (Vetamine; Mallinckrodt Veterinary, Mundelein, IL), followed by inhaled methoxyflurane (Metafane; Mallinckrodt Veterinary). Under sterile conditions, the cecum was exposed through a 1- to 2-cm incision of the lower left abdomen, ligated tightly with a 3-0 silk suture without causing bowel obstruction, and then punctured through and through once with a 21-gauge needle. The cecum was replaced in the peritoneal cavity and the incision was closed with surgical staples. The mice then received 1 ml of saline s.c. for fluid resuscitation, and placed on a heating pad until they recovered from the anesthesia.
Neutralization of MCP-1
To neutralize MCP-1 activity, 0.5 ml of anti-murine MCP-1 antiserum was injected i.p. 2 h prior to CLP. The volume of antiserum was considered to be sufficient, because a larger volume (1 ml) or repeated injections of the antiserum (twice with 0.5 ml; -2 and 48 h after CLP) did not induce further biological effects (data not shown). Furthermore, the biological half-life of the Ab was approximately 36 h (C. M. Hogaboam, personal observations). Polyclonal anti-murine MCP-1 antiserum was raised by immunizing rabbits with murine rMCP-1 (R&D Systems, Minneapolis, MN) (16). The Abs did not cross-react with a number of other murine cytokines including CXC and CC chemokines, since MCP-1 ELISA established with the Abs did not detect any murine cytokines at a concentration of as high as 100 ng/ml. The Abs had a neutralizing activity against murine rMCP-1 in in vitro chemotaxis assay. In addition, previous reports showed that administration of anti-MCP-1 antiserum effectively and specifically neutralized MCP-1 activity in vivo (16, 17, 18, 19, 20). As a control, preimmune rabbit serum (0.5 ml) was used.
Experimental protocol
In the first set of experiments, the mice were observed for 7 days after CLP to determine the mortality rate induced with CLP. In the second set of experiments, the CLP mice were anesthetized, bled, and euthanized at 4, 8, 24, and 48 h after CLP. The peritoneal cavities were washed with 2 ml of sterile saline, and the lavage fluids were collected. After taking a 10-µl aliquot of lavage fluids for assessment of bacteria CFUs, the fluids were centrifuged at 6000 x g for 1 min at 4°C. Cellfree peritoneal fluids were stored at -20°C. Cell pellets were resuspended in saline and the cell numbers were counted in a hemocytometer. Smear slides were prepared with a Cytospin 2 (Shandon, Pittsburgh, PA), and differential cell analyses were made after Diff-Quik staining (Dade, Düdingen, Switzerland). In some mice, 30 mg/kg of a specific LTB4 receptor antagonist CP-105,696 (Pfizer, Groton, CT, gift of H. J. Showell) or vehicle was administered orally 2 h prior to CLP surgery. CP-105,696 is a selective and potent LTB4 receptor antagonist, which is effective in reducing the severity of collagen-induced arthritis and experimental allergic encephalomyelitis in mice (21, 22). To assess the in vivo effect of murine rMCP-1, 0.5 µg of either MCP-1 or vehicle was i.p. injected into normal mice.
Determination of CFU
Ten microliters of peritoneal lavage fluid and peripheral blood from each mouse was placed on ice and serially diluted with sterile saline. Ten microliters of each dilution was plated on thymic-shared Ag (TSA) blood agar plates (Difco, Detroit, MI) and incubated overnight at 37°C, after which the number of colonies was counted. Data were expressed as CFU/10 µl.
Chemokine and LTB4 measurements
Murine MIP-1, MIP-2, KC, and MCP-1 were measured by using
double-ligand ELISA, as previously described in detail (9, 16). The ELISAs did not cross-react with other murine cytokines,
and consistently detected murine cytokine concentrations above 25
pg/ml. Measurements of LTB4 in peritoneal fluids were
quantified by using a competitive enzyme immunoassay (R&D Systems),
according to the manufacturer’s instruction. The lower detection limit
was 200 pg/ml.
Cell culture
Peritoneal cells were harvested from normal mice, washed, and the cells (1 x 106 cells) were incubated at 37°C in 24-well culture dishes. One hour later, nonadherent cells were removed and the medium (RPMI 1640 containing 10% FCS and antibiotics) was replaced. The adherent cells were stimulated with various concentrations of murine MCP-1 or 1 µg/ml Escherichia coli LPS (0111, B4: Difco), and incubated for 18 h at 37°C. The culture medium was collected, centrifuged at 6000 x g for 1 min at 4°C, and then the supernatant assayed for LTB4.
Statistics
Statistical significance was evaluated by a two-tailed unpaired Student’s t test. In case of survival curve and CFU count, the data were analyzed by the log-rank test and Mann-Whitney test, respectively. A p value <0.05 was regarded as statistically significant. All data were expressed as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Investigations were first established to determine the leukocyte
infiltration into the peritoneal cavity post-CLP. As shown in Fig. 1
, CLP induced a rapid peritonitis
composed of various leukocyte subpopulations. The number of total
infiltrating leukocytes reached the peak level at 8 h, and
decreased after 24 h (Fig. 1). Differential cell analyses
demonstrated that the accumulation of neutrophils peaked at 8 h,
while the number of macrophages peaked at 24 h. Similar levels of
macrophages still remained at 48 h. The accumulation of
lymphocytes gradually increased with time (Fig. 1). These studies
demonstrate that a temporal pattern of leukocyte infiltration into the
peritoneum occurs after CLP that reflects an early neutrophil
infiltrate followed by the elicitation of macrophages and
lymphocytes.
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Previous investigations demonstrated that certain CXC chemokines,
such as MIP-2, were elevated in the peritoneal fluids during the
evolution of CLP-induced peritonitis (9); thus,
experiments were next conducted to assess peritoneal fluid levels of
the CC chemokine, MCP-1. During the evolution of CLP-induced
peritonitis, levels of MCP-1 in the peritoneal fluids were detectable
by 4 h, peaked at 8 h (94.6 ± 21.9 ng/cavity,
n = 6), and then rapidly declined (Fig. 2A). Interestingly, the peak
levels of MCP-1 in the peritoneum were extremely high, preceded the
peak in the recruitment of macrophages by 16 h, and were
coincident with the peak in neutrophil levels. Upon further analyses,
MCP-1 levels in sera were found to peak at 8 h (1.9 ± 0.3
ng/ml, n = 6), but were much lower than those found in
the peritoneal fluids (Fig. 2B), suggesting that the MCP-1
was produced in greater abundance in the peritoneum. These data
indicate that MCP-1 levels were augmented during the evolution of
CLP-induced peritonitis.
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To examine the contribution of MCP-1 during the evolution of
CLP-induced peritonitis leading to lethality, either anti-MCP-1
antiserum or control serum was i.p. injected 2 h prior to CLP
surgery, and the survival rates were monitored. As shown in Fig. 3, neutralization of MCP-1 significantly
deteriorated the survival of mice following CLP. At 24 h post-CLP,
92% of control mice (24 of 26 mice) were alive compared with 67% in
anti-MCP-1 antiserum-treated mice (20 of 30 mice). The detrimental
effects of neutralizing MCP-1 were most apparent at 48 h. At this
time point, the mortality rate in control mice was 27% (7 of 26 mice),
however, a striking 67% mortality rate (20 of 30 mice) was observed in
mice that received anti-MCP-1 antiserum (Fig. 3). These findings
suggest that endogenous MCP-1 may have a protective role in CLP-induced
lethality, as removal of murine MCP-1 resulted in an increase in the
mortality.
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In an attempt to identify the mechanism whereby MCP-1 may exhibit
a beneficial effect during the development of CLP-induced peritonitis,
we determined the bacterial load in the peritoneal fluids and sera of
mice treated with either anti-MCP-1 antiserum or control serum. No
bacteria were recovered from peritoneal fluid samples collected at 4
and 8 h after CLP in either the anti-MCP-1- or control
serum-treated groups. However, peritoneal fluids from the 24-h time
point contained a significant number of bacteria in 8 of 14 mice
receiving control serum (mean CFUs 1.1 x 105/10 µl
peritoneal fluid) (Fig. 4). At this same
time point, animals treated with anti-MCP-1 antiserum and
developing CLP-induced peritonitis had a 65-fold increase in bacteria
recovered from the peritoneal fluids (11 of 14 mice, mean CFU =
7.1 x 106/10 µl, p < 0.01) when
compared with controls (Fig. 4). In addition, 2 of 14 mice presented
with a bacteremia at 24 h in the CLP animals treated with
anti-MCP-1 antiserum. These studies support a host defense role for
endogenous MCP-1 during experimental sepsis, as neutralization of MCP-1
resulted in a reduced ability to clear bacteria from the
peritoneum.
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In order to assess the in vivo contribution of MCP-1 on leukocyte
infiltration during the evolution of CLP-induced peritonitis, mice were
treated with neutralizing anti-MCP-1 antiserum and total leukocyte
numbers were determined. As shown in Fig. 5A, neutralization of MCP-1
resulted in a decreased number of total leukocytes at 8 h after
CLP. Furthermore, differential cell analyses demonstrated that the
recruitment of both neutrophils and macrophages were reduced by
anti-MCP-1 antiserum by 61% and 53%, respectively (Fig. 5, B and C). At the 24-h time point, no significant
differences were found regarding the recruitment of total leukocytes,
neutrophils, and macrophages between anti-MCP-1 antiserum or
control serum-treated animals (Fig. 5, A–C).
There was no significant difference in the recruitment of lymphocytes
for up to 24 h (data not shown).
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To determine the effect of endogenous MCP-1 on the production of
other chemokines in the peritoneum, levels of specific chemokines in
the peritoneal fluids were analyzed after treatment with anti-MCP-1
antiserum or control serum. The levels of KC, MIP-1, and MIP-2
increased in the peritoneal fluids after CLP, which peaked at 4, 8, and
24 h post-CLP, respectively. Interestingly, the peak amounts of
these chemokines were much lower than the peak amount of MCP-1, which
was detected at 8 h after CLP (MCP-1: 94.6 ± 21.9 ng/cavity,
n = 6; KC: 7.9 ± 1.9 ng/cavity, n
= 6; MIP-1: 0.9 ± 0.2 ng/cavity, n = 6; MIP-2:
2.3 ± 0.8 ng/cavity, n = 6). The levels of these
chemokines were not inhibited with anti-MCP-1 antiserum throughout
the observation periods. In addition, the levels of other cytokines
found in the peritoneal fluids, which included TNF-, IFN-
, IL-10,
IL-12, and IL-13, were not affected by anti-MCP-1 antiserum (data
not shown).
MCP-1 stimulates the production of LTB4
The above studies indicated that the neutralization of MCP-1
resulted in a significant decrease in neutrophil numbers after
CLP-induced peritonitis. In order to determine the mechanism underlying
this observation, we assessed the ability of anti-MCP-1 antiserum
to alter the levels of a known neutrophil chemotactic factor,
LTB4. As shown in Fig. 6A, administration of
anti-MCP-1 antiserum significantly decreased the production of
LTB4 in the peritoneal fluids at 4 and 8 h by 63 and
59%, respectively, as compared with preimmune serum. Conversely,
normal mice challenged i.p. with murine MCP-1 were found to have a
higher level of LTB4 in the peritoneal fluids (Fig. 6B). When peritoneal macrophages were cultured in vitro,
murine MCP-1 induced the production of LTB4 in a
dose-dependent manner, and the peak levels of LTB4 after
MCP-1 stimulation were similar to that induced with LPS (Fig. 7). To elucidate, if neutrophil
infiltration in CLP mice was mediated by LTB4, a specific
LTB4 receptor antagonist was administered orally 2 h
prior to CLP surgery and the numbers of infiltrating leukocytes were
assessed at the 8-h time point. Treatment with the LTB4
receptor antagonist inhibited the recruitment of both neutrophils and
macrophages by 36 and 48%, respectively (Fig. 8A). Interestingly, the levels
of MCP-1 in peritoneal fluids were also reduced with LTB4
receptor antagonist by 51% (Fig. 8B). To elucidate the role
of LTB4 in the survival of mice following CLP, the
LTB4 receptor antagonist was next administered orally
2 h prior to CLP and every 24 h after CLP, and the survival
rate was monitored. As shown in Fig. 9,
LTB4 blockade dramatically decreased the survival of mice
following CLP. At 72 h after CLP, a striking 100% mortality rate
(20 of 20 mice) was observed in mice that received LTB4
receptor antagonist whereas the mortality rate of control mice was 65%
(13 of 20 mice) (Fig. 9). Thus, LTB4 appears to be an
important mediator involved in the recruitment of leukocytes and
CLP-induced lethality, and the production of this lipid mediator is
regulated by MCP-1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1, are
deleterious, while anti-inflammatory cytokines, such as IL-4,
IL-10, and IL-13, are beneficial in attenuating the mortality in this
model (11). In addition to these latter regulatory
cytokines, we recently demonstrated that rMCP-1 protected mice in a
model of lethal endotoxemia (17). However, clinical sepsis
is much more complex than an experimental model of endotoxemia in which
animals receive a single injection of endotoxin. For example,
neutralization of TNF- was not efficacious for the treatment of
either human sepsis or experimental sepsis induced by CLP (23, 24). In additional experimental studies, the administration of
IL-1 improved survival following CLP (25), which
corresponded with clinical observations that the inhibition of IL-1
with IL-1R antagonist failed to improve survival in large scale trials
involving human sepsis (26). In the present study, we have
extended this cytokine theme and have examined the regulatory role of
the chemokine MCP-1 in an experimental model of sepsis induced by CLP.
Our investigations demonstrate that endogenous levels of MCP-1 are
highly elevated in peritoneal fluids post-CLP. The contribution of
MCP-1 was determined via in vivo neutralization studies, which
demonstrated that depletion of MCP-1 resulted in enhanced lethality.
These investigations indicate that endogenous MCP-1 is protective in
septic peritonitis induced by CLP. The recruitment of leukocytes into the infectious foci is an essential mechanism of our host defense system necessary to eliminate invading pathogens. One mechanism whereby endogenous MCP-1 exerts a protective role in experimental septic peritonitis appears to occur by the recruitment and subsequent activation of leukocytes. In our model of CLP-induced peritonitis, administration of anti-MCP-1 antiserum inhibited the recruitment of both macrophages and neutrophils at 8 h. However, by 24 h post-CLP, anti-MCP-1 antiserum treatment failed to reduce the accumulation of leukocytes. Interestingly, at this time point (24 h) there was an increase in viable bacteria recovered from the peritoneal cavity, suggesting that the bacteria-clearing activity of the leukocytes was impaired by this treatment. In addition to its chemotactic properties, MCP-1 can activate monocytes and cause lysozomal enzyme release (27) and H2O2 production (28), both of which are effector molecules for bacterial killing. Furthermore, earlier studies have demonstrated that an i.p. injection of MCP-1 augmented the killing activity of peritoneal macrophages without promoting an increase in the elicitation of macrophages (29). Thus, neutralization of MCP-1 can both decrease the elicitation of leukocytes and alter leukocyte activation.
During the evolution of the CLP-induced peritonitis, the recruitment of
neutrophils in the peritoneum was inhibited with anti-MCP-1
antiserum, despite the fact that MCP-1 has no neutrophil chemotactic
activity in vitro (30). This phenomenon is consistent with
a previous report showing that neutralization of MCP-1 reduced the
influx of neutrophils in a pulmonary Cryptococcus neoformans
infection (18), but the mechanism in this study was not
addressed. Since the peritoneal macrophages (5.4 ± 0.6 x
106/cavity, n = 13) are present even in
normal conditions, it is quite reasonable to speculate that MCP-1
attracts neutrophils indirectly via the activation of the resident
macrophages, which are expected to be the cellular source of many
inflammatory cytokines and chemokines. Once macrophages are activated,
enhanced MCP-1 production can occur via stimulation with such bacterial
component as muramyl dipeptide and/or LPS. In addition, cytokine
cascades are likely to be established with the subsequent induction of
chemokines. Therefore, we measured the production of TNF- and the
following chemokines: MIP-2, KC, and MIP-1. Neither the levels of
these mediators nor the production of putative immunoregulatory
cytokines, such as IL-10 and IL-13, were changed by anti-MCP-1
antiserum treatment. Another immunoregulatory cytokine, IL-4, was not
detected in the peritoneum at any time point examined. Thus, the
inhibitory effects of anti-MCP-1 on the recruitment of neutrophils
in CLP animals appear to be independent of a cytokine pathway.
Additional studies were performed to determine the influence of MCP-1 depletion on the levels of LTB4, a known neutrophil chemotactic and activating factor (31). In these studies, 59% of LTB4 normally expressed in the peritoneum at 8 h after CLP was inhibited by anti-MCP-1 antiserum. These data strongly suggest that anti-MCP-1 inhibited neutrophil influx via the down-regulation of LTB4 production in this model. Accordingly, the recruitment of neutrophils post-CLP was inhibited with a specific LTB4 receptor antagonist. Since LTB4 can be generated by leukocytes from arachidonic acid (31), and anti-MCP-1 antiserum inhibited the recruitment of leukocytes, it might be possible that the reduced level of LTB4 was the result of the reduced number of infiltrating leukocytes; however, the inhibition began at 4 h, a time when the recruitment of leukocytes was not inhibited. In vivo studies demonstrated that the i.p. injection of MCP-1 induced the production of LTB4, while in vitro analyses showed that MCP-1 dose-dependently stimulated the production of LTB4 from peritoneal macrophages. These studies suggest that MCP-1 induces neutrophil elicitation indirectly via the production of LTB4 in this model.
An LTB4 receptor antagonist also inhibited the recruitment of macrophages. LTB4 attracts not only neutrophils, but also monocytes (32). Interestingly, the level of MCP-1 in the peritoneum after CLP was inhibited by 51% by the LTB4 receptor antagonist, suggesting that the inhibition of the recruitment of macrophages by the LTB4 receptor antagonist occurred, at least in part, via the reduced production of MCP-1. Our results suggest that MCP-1 and LTB4 affect the production of each other, thus amplifying the local inflammatory responses. Administration of MCP-1 enhanced bacterial clearance following i.p. challenge of viable Salmonella typhimurium and Pseudomonas aeruginosa, and protected mice from the lethality (29). Exogenous LTB4 enhanced bacterial clearance in the same infectious model (33), and leukotriene-deficient mice manifested a greater degree of lethality as well as bacteremia following Klebsiella pneumoniae challenge (34). In our model of septic peritonitis, administration of LTB4 receptor antagonist was detrimental to the survival of mice post-CLP. Collectively, inflammatory responses induced and amplified by MCP-1 and LTB4 appear to be indispensable to protect mice from CLP-induced lethality.
In summary, neutralization of MCP-1 increased lethality in an experimental model of septic peritonitis, which was associated with the reduction in the recruitment and activation of both macrophages and neutrophils. While previous studies unequivocally demonstrated that MCP-1 could directly elicit macrophages, our experiments show that MCP-1 can indirectly elicit neutrophils during in vivo inflammatory responses via augmenting levels of LTB4. Thus, endogenous MCP-1 appears to possess a beneficial effect during the evolution of experimental sepsis by eliciting various leukocyte subpopulations needed to locally contain the initial traumatic insult and eliminate microbes.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Steven L. Kunkel, Department of Pathology, University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602. E-mail address:
3 Abbreviations used in this paper: MIP-2, macrophage-inflammatory protein-2; MCP, monocyte chemoattractant protein; CLP, cecal ligation and puncture; LTB4, leukotriene B4; TSA, thymic-shared Ag.
Received for publication April 29, 1999. Accepted for publication September 13, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and granulocyte elastase release in human secondary peritonitis. Cytokine 9:288.[Medline]
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 M. C. Dessing, A. F. de Vos, S. Florquin, and T. van der Poll Monocyte Chemoattractant Protein 1 Does Not Contribute to Protective Immunity against Pneumococcal Pneumonia Infect. Immun., December 1, 2006; 74(12): 7021 - 7023. [Abstract] [Full Text] [PDF]
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H. Weighardt, S. Kaiser-Moore, S. Schlautkotter, T. Rossmann-Bloeck, U. Schleicher, C. Bogdan, and B. Holzmann Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis J. Immunol., October 15, 2006; 177(8): 5623 - 5630. [Abstract] [Full Text] [PDF]
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 F. Hildebrand, W. J. Hubbard, M. A. Choudhry, M. Frink, H.-C. Pape, S. L. Kunkel, and I. H. Chaudry Kupffer Cells and Their Mediators: The Culprits in Producing Distant Organ Damage after Trauma-Hemorrhage Am. J. Pathol., September 1, 2006; 169(3): 784 - 794. [Abstract] [Full Text] [PDF]
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H. Qiu, A.-S. Johansson, M. Sjostrom, M. Wan, O. Schroder, J. Palmblad, and J. Z. Haeggstrom Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B4 PNAS, May 2, 2006; 103(18): 6913 - 6918. [Abstract] [Full Text] [PDF]
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 M. Heesen, R. Renckens, A. F. de Vos, D. Kunz, and T. van der Poll Human Endotoxemia Induces Down-Regulation of Monocyte CC Chemokine Receptor 2 Clin. Vaccine Immunol., January 1, 2006; 13(1): 156 - 159. [Abstract] [Full Text] [PDF]
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 S. B. Pruett, Q. Zheng, C. Schwab, and R. Fan Sodium Methyldithiocarbamate Inhibits MAP Kinase Activation through Toll-like Receptor 4, Alters Cytokine Production by Mouse Peritoneal Macrophages, and Suppresses Innate Immunity Toxicol. Sci., September 1, 2005; 87(1): 75 - 85. [Abstract] [Full Text] [PDF]
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J. K. S. Ko and C.-H. Cho The Diverse Actions of Nicotine and Different Extracted Fractions from Tobacco Smoke against Hapten-Induced Colitis in Rats Toxicol. Sci., September 1, 2005; 87(1): 285 - 295. [Abstract] [Full Text] [PDF]
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 N. Miyahara, K. Takeda, S. Miyahara, S. Matsubara, T. Koya, A. Joetham, E. Krishnan, A. Dakhama, B. Haribabu, and E. W. Gelfand Requirement for Leukotriene B4 Receptor 1 in Allergen-induced Airway Hyperresponsiveness Am. J. Respir. Crit. Care Med., July 15, 2005; 172(2): 161 - 167. [Abstract] [Full Text] [PDF]
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C. D. L. Ramos, C. Canetti, J. T. Souto, J. S. Silva, C. M. Hogaboam, S. H. Ferreira, and F. Q. Cunha MIP-1{alpha}[CCL3] acting on the CCR1 receptor mediates neutrophil migration in immune inflammation via sequential release of TNF-{alpha} and LTB4 J. Leukoc. Biol., July 1, 2005; 78(1): 167 - 177. [Abstract] [Full Text] [PDF]
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A. Pettersson, A. Sabirsh, J. Bristulf, K. Kidd-Ljunggren, B. Ljungberg, C. Owman, and U. Karlsson Pro- and anti-inflammatory substances modulate expression of the leukotriene B4 receptor, BLT1, in human monocytes J. Leukoc. Biol., June 1, 2005; 77(6): 1018 - 1025. [Abstract] [Full Text] [PDF]
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C. L. Speyer, H. Gao, N. J. Rancilio, T. A. Neff, G. B. Huffnagle, J. V. Sarma, and P. A. Ward Novel Chemokine Responsiveness and Mobilization of Neutrophils during Sepsis Am. J. Pathol., December 1, 2004; 165(6): 2187 - 2196. [Abstract] [Full Text] [PDF]
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T. L. Ness, K. J. Carpenter, J. L. Ewing, C. J. Gerard, C. M. Hogaboam, and S. L. Kunkel CCR1 and CC Chemokine Ligand 5 Interactions Exacerbate Innate Immune Responses during Sepsis J. Immunol., December 1, 2004; 173(11): 6938 - 6948. [Abstract] [Full Text] [PDF]
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 M. Mehrabian and H. Allayee Vascular Cross-Talk: A Conversation Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1748 - 1749. [Full Text] [PDF]
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L. Huang, A. Zhao, F. Wong, J. M. Ayala, M. Struthers, F. Ujjainwalla, S. D. Wright, M. S. Springer, J. Evans, and J. Cui Leukotriene B4 Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1783 - 1788. [Abstract] [Full Text] [PDF]
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M. J. Scott, W. G. Cheadle, J. J. Hoth, J. C. Peyton, K. Subbarao, W.-H. Shao, and B. Haribabu Leukotriene B4 Receptor (BLT-1) Modulates Neutrophil Influx into the Peritoneum but Not the Lung and Liver during Surgically Induced Bacterial Peritonitis in Mice Clin. Vaccine Immunol., September 1, 2004; 11(5): 936 - 941. [Abstract] [Full Text] [PDF]
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K. Subbarao, V. R. Jala, S. Mathis, J. Suttles, W. Zacharias, J. Ahamed, H. Ali, M. T. Tseng, and B. Haribabu Role of Leukotriene B4 Receptors in the Development of Atherosclerosis: Potential Mechanisms Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 369 - 375. [Abstract] [Full Text]
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C. L. Speyer, T. A. Neff, R. L. Warner, R.-F. Guo, J. V. Sarma, N. C. Riedemann, M. E. Murphy, H. S. Murphy, and P. A. Ward Regulatory Effects of iNOS on Acute Lung Inflammatory Responses in Mice Am. J. Pathol., December 1, 2003; 163(6): 2319 - 2328. [Abstract] [Full Text]
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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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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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M. H. Tarlowe, K. B. Kannan, K. Itagaki, J. M. Adams, D. H. Livingston, and C. J. Hauser Inflammatory Chemoreceptor Cross-Talk Suppresses Leukotriene B4 Receptor 1-Mediated Neutrophil Calcium Mobilization and Chemotaxis After Trauma J. Immunol., August 15, 2003; 171(4): 2066 - 2073. [Abstract] [Full Text] [PDF]
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M. L. deSchoolmeester, M. C. Little, B. J. Rollins, and K. J. Else Absence of CC Chemokine Ligand 2 Results in an Altered Th1/Th2 Cytokine Balance and Failure to Expel Trichuris muris Infection J. Immunol., May 1, 2003; 170(9): 4693 - 4700. [Abstract] [Full Text] [PDF]
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 B. B. Vargaftig and M. Singer Leukotrienes, IL-13, and chemokines cooperate to induce BHR and mucus in allergic mouse lungs Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L260 - L269. [Abstract] [Full Text] [PDF]
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 M. Mehrabian, H. Allayee, J. Wong, W. Shih, X.-P. Wang, Z. Shaposhnik, C. D. Funk, and A. J. Lusis Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice Circ. Res., July 26, 2002; 91(2): 120 - 126. [Abstract] [Full Text] [PDF]
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 N. Tuaillon, D. F. Shen, R. B. Berger, B. Lu, B. J. Rollins, and C.-C. Chan MCP-1 Expression in Endotoxin-Induced Uveitis Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1493 - 1498. [Abstract] [Full Text] [PDF]
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A. R. Silva, E. F. de Assis, L. F. C. Caiado, G. K. Marathe, M. T. Bozza, T. M. McIntyre, G. A. Zimmerman, S. M. Prescott, P. T. Bozza, and H. C. Castro-Faria-Neto Monocyte Chemoattractant Protein-1 and 5-Lipoxygenase Products Recruit Leukocytes in Response to Platelet-Activating Factor-Like Lipids in Oxidized Low-Density Lipoprotein J. Immunol., April 15, 2002; 168(8): 4112 - 4120. [Abstract] [Full Text] [PDF]
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M. E. Rosenfeld Leukocyte Recruitment Into Developing Atherosclerotic Lesions: The Complex Interaction Between Multiple Molecules Keeps Getting More Complex Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 361 - 363. [Full Text] [PDF]
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R. J. Aiello, P.-A. Bourassa, S. Lindsey, W. Weng, A. Freeman, and H. J. Showell Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 443 - 449. [Abstract] [Full Text] [PDF]
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 C.-H. Woo, H.-J. You, S.-H. Cho, Y.-W. Eom, J.-S. Chun, Y.-J. Yoo, and J.-H. Kim Leukotriene B4 Stimulates Rac-ERK Cascade to Generate Reactive Oxygen Species That Mediates Chemotaxis J. Biol. Chem., March 1, 2002; 277(10): 8572 - 8578. [Abstract] [Full Text] [PDF]
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J. M. Schuh, K. Blease, and C. M. Hogaboam CXCR2 Is Necessary for the Development and Persistence of Chronic Fungal Asthma in Mice J. Immunol., February 1, 2002; 168(3): 1447 - 1456. [Abstract] [Full Text] [PDF]
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J. A. Jordan, R.-F. Guo, E. C. Yun, V. Sarma, R. L. Warner, L. D. Crouch, G. Senaldi, T. R. Ulich, and P. A. Ward Role of IL-18 in Acute Lung Inflammation J. Immunol., December 15, 2001; 167(12): 7060 - 7068. [Abstract] [Full Text] [PDF]
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P. W. Finn, J. R. Stone, M. R. Boothby, and D. L. Perkins Inhibition of NF-{kappa}B-Dependent T Cell Activation Abrogates Acute Allograft Rejection J. Immunol., November 15, 2001; 167(10): 5994 - 6001. [Abstract] [Full Text] [PDF]
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 S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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 A. Matsukawa, M. H. Kaplan, C. M. Hogaboam, N. W. Lukacs, and S. L. Kunkel Pivotal Role of Signal Transducer and Activator of Transcription (Stat)4 and Stat6 in the Innate Immune Response during Sepsis J. Exp. Med., March 12, 2001; 193(6): 679 - 688. [Abstract] [Full Text] [PDF]
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K. Blease, B. Mehrad, N. W. Lukacs, S. L. Kunkel, T. J. Standiford, and C. M. Hogaboam Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure to Asperigillus fumigatus Conidia J. Immunol., February 1, 2001; 166(3): 1832 - 1842. [Abstract] [Full Text] [PDF]
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M. L. Steinhauser, C. M. Hogaboam, A. Matsukawa, N. W. Lukacs, R. M. Strieter, and S. L. Kunkel Chemokine C10 Promotes Disease Resolution and Survival in an Experimental Model of Bacterial Sepsis Infect. Immun., November 1, 2000; 68(11): 6108 - 6114. [Abstract] [Full Text] [PDF]
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C. L. Bone-Larson, C. M. Hogaboam, M. L. Steinhauser, S. H. P. Oliveira, N. W. Lukacs, R. M. Strieter, and S. L. Kunkel Novel Protective Effects of Stem Cell Factor in a Murine Model of Acute Septic Peritonitis : Dependence on MCP-1 Am. J. Pathol., October 1, 2000; 157(4): 1177 - 1186. [Abstract] [Full Text] [PDF]
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B. Haribabu, M. W. Verghese, D. A. Steeber, D. D. Sellars, C. B. Bock, and R. Snyderman Targeted Disruption of the Leukotriene B4 Receptor in Mice Reveals Its Role in Inflammation and Platelet-activating Factor-induced Anaphylaxis J. Exp. Med., August 8, 2000; 192(3): 433 - 438. [Abstract] [Full Text] [PDF]
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A. Matsukawa, C. M. Hogaboam, N. W. Lukacs, P. M. Lincoln, H. L. Evanoff, and S. L. Kunkel Pivotal Role of the CC Chemokine, Macrophage-Derived Chemokine, in the Innate Immune Response J. Immunol., May 15, 2000; 164(10): 5362 - 5368. [Abstract] [Full Text] [PDF]
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 A. Turler, N. T. Schwarz, E. Turler, J. C. Kalff, and A. J. Bauer MCP-1 causes leukocyte recruitment and subsequently endotoxemic ileus in rat Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G145 - G155. [Abstract] [Full Text] [PDF]
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), macrophages (
),
and lymphocytes (
) were then counted. Differential cell analyses
were determined by Diff-Quik-stained smears. Each point represents the
mean ± SEM of six estimations from separate mice (total mice:
24).
, p < 0.05, when compared
with control. B, Murine MCP-1 (0.5 µg) (
