| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
*
Pathology and
Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, in favor of IL-10. This cytokine shift corresponded to changes
in bacterial load, as CLP mice receiving IL-12 antiserum yielded more
CFUs from the peritoneal cavity at 24 h after CLP. To address the
role of bacterial infection in IL-12 antiserum-induced mortality
following CLP, antibiotics were administered for 4 days after surgery.
Despite regular antibiotic administration, IL-12 immunoneutralization
still reduced survival in CLP mice. Furthermore, histology of the ceca
revealed that mice administered IL-12 antisera failed to show typical
organization of the damaged cecum wall. Accordingly, Gram staining
revealed bacteria within peritoneal fluids from these mice, while
peritoneal fluids from CLP mice that received preimmune serum and
antibiotics were free of bacteria. Altogether, these data suggested
multiple important roles for IL-12 in the evolution of murine septic
peritonitis. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-1. These
host-derived, early response cytokines initiate a cascade of
inflammatory cytokines, which together mediate the hemodynamic changes
and inflammatory events that typify sepsis (4). IL-12
plays a critical role in this early inflammatory process by augmenting
the production of IFN- and other cytokines from NK and T cells, by
enhancing the cytolytic activity of CTLs and NK cells, and by
stimulating the proliferation of activated T and NK cells
(5). Furthermore, IL-12 appears to be a vital component of
the host defense against both Gram-positive and Gram-negative bacterial
organisms, as evidenced by the heightened host resistance conferred by
IL-12 administration in several bacterial infection models
(6, 7, 8, 9, 10). However, the proinflammatory effects of IL-12 can
become detrimental during sepsis. The exaggerated proinflammatory
response often associated with IL-12 production during sepsis may
result in many of the injurious and sometimes fatal physiological
symptoms of the disease (11, 12).
Host-derived, anti-inflammatory mediators like IL-10 counterbalance
the IL-12-mediated inflammatory responses to bacterial pathogens. For
example, IL-10 exerts potent in vitro and in vivo antiinflammatory
effects, in part, by suppressing the production of proinflammatory
cytokines, including TNF-, IL-1, and IFN-, and by repressing
macrophage and neutrophil phagocytic and bactericidal activities
(13, 14, 15). Various studies have shown that a septic
response dominated by proinflammatory cytokines is toxic. Conversely,
tipping the cytokine balance in favor of an anti-inflammatory
response with either IL-10 treatment or IL-12 neutralization has proved
beneficial in various sepsis models (13, 16, 17, 18); however,
in a murine model of neonatal, bacterial sepsis, IL-12 neutralization
was clearly detrimental, suggesting that the severe suppression of
proinflammatory mediators may also harm septic humans
(19).
In this study, we explored the role of IL-12 in a clinically relevant
model of bacterial sepsis, namely cecal ligation and puncture
(CLP).3 The CLP mouse serves as a
clinically relevant disease model, because it mimics the septic
response sometimes associated with postsurgical or accidental trauma.
Furthermore, this model meets the two general diagnostic criteria for
sepsis, as the CLP mice display systemic inflammation akin to the human
systemic inflammatory response syndrome and experience an active
bacterial infection (1). In the CLP model, IL-12
neutralization was clearly detrimental. Thus, subsequent experiments
were designed in an attempt to delineate a mechanistic role for IL-12
in this model. Previously it has been shown that IL-12 and IL-10
antagonize each other in Th cell-mediated immune responses (20, 21). In
this study, we clearly show that IL-12 can also balance IL-10 in the
context of an innate immune response, as IL-12 immunoneutralization
results in a cytokine profile dominated by IL-10 with insufficient
IL-12 and IFN-. Furthermore, disrupting IL-12 levels produces a
cascade of events that ultimately blocks bacterial clearance and tissue
repair. These studies support the vital role of IL-12 in the host
response during experimental sepsis in which the host faces the dual
threat of pathophysiological imbalances and bacterial colonization.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Specific pathogen-free CD-1 mice (6- to 12-wk-old females, Charles River Breeding Laboratories, Wilmington, MA) were used in all experiments. All mice were housed in specific pathogen-free conditions within the animal care facility at the University of Michigan Unit for Laboratory Animal Medicine (ULAM, Ann Arbor, MI) until the day of sacrifice.
Animal model
The CLP model was used as previously described (17). The mice were anesthetized by i.p. injection with 3–3.5 mg of ketamine HCl (Ketaset, Fort Dodge Laboratories, Fort Dodge, IA) followed by inhaled methoxyflurane (Metafane, Pitman-Moore, Mundelein, IL) as needed. The mice were given a 1- to 2-cm longitudinal incision to the lower left quadrant of the abdomen. The cecum was exposed and the distal one-third was ligated with 3-0 silk suture, and punctured through and through with a 21-gauge needle. The cecum was then replaced in the peritoneal cavity and the incision was closed with surgical staples. In sham controls, the cecum was exposed but not ligated or punctured, then returned to the abdominal cavity. All mice were administered 1 ml of sterile saline s.c. as a fluid resuscitation measure immediately following surgery.
Murine cytokine ELISA
Murine IFN-, IL-12, and IL-10 were quantitated using a
modification of a double-ligand method as previously described
(22). Briefly, flat-bottom 96-well microtiter plates
(Immuno-Plate I 96-F; Nunc, Glostrup, Denmark) were coated with 50
µl/well of rabbit Ab against the various cytokines (1 µg/ml in 0.6
M NaCl, 0.26 M H3BO4, and 0.08 M NaOH, pH 9.6)
for 16 h at 4°C and then washed with PBS, pH 7.5, 0.05%
Tween-20 (wash buffer). Microtiter plate nonspecific-binding sites were
blocked with 2% BSA in PBS and incubated for 90 min at 37°C. Plates
were rinsed four times with wash buffer and diluted (neat and 1:10)
cell-free supernatants (50 µl) in duplicate were added, followed by
incubation for 1 h at 37°C. Plates were washed four times,
followed by the addition of 50 µl/well biotinylated rabbit Abs
against the specific cytokines (3.5 µg/ml in PBS (pH 7.5), 0.05%
Tween-20, and 2% FCS), and plates incubated for 30 min at 37°C.
Plates were washed four times, Streptavidin-peroxidase conjugate
(Bio-Rad Laboratories, Richmond, CA) was added, and the plates were
incubated for 30 min at 37°C. Plates were washed again four times and
chromogen substrate (Bio-Rad Laboratories) was added. The plates were
incubated at room temperature to the desired extinction, and the
reaction was terminated with 50 µl/well of 3 M
H2SO4 solution. Plates were read at 490 nm in
an ELISA reader. Standards were 1/2 log dilutions of recombinant
murine cytokines from 1 pg/ml to 100 ng/ml. This ELISA method
consistently detected murine cytokine concentrations above 25 pg/ml,
and ELISA specificity was confirmed for each cytokine and chemokine
measured.
Determination of peritoneal CFU
At the time of sacrifice, the abdominal wall was exposed. Two milliliters of sterile saline was injected into the peritoneal cavity. The peritoneal cavity was then opened, and peritoneal wash fluids were aseptically collected and placed on ice. Serial 1:10 dilutions of peritoneal lavage samples were made. Ten microliters of each dilution was plated on soy base blood agar plates (Difco, Detroit, MI). Plates were incubated for 18 h at 37°C, after which colonies were counted.
Gram staining of peritoneal washings
Peritoneal wash samples were cytospun onto microscopy slides, and the slides were allowed to air dry. Prior to staining, the samples were heat fixed for approximately 10 s. All staining reagents were contained in a Gram Stain Kit (Fisher Scientific, Orangeburg, NY).
Reagents
As previously described, cytokine-specific Abs were generated in
our laboratory for use in ELISAs and in immunoneutralization
experiments (23). Briefly, polyclonal IL-12-, IL-10-, and
IFN--specific antiseras were generated in New Zealand White rabbits
by multiple site immunization with the appropriate recombinant murine
cytokine (R&D Systems, Minneapolis, MN) and adjuvant. Polyclonal Abs
were titered by direct ELISA, and Ab specificity was verified for each
ELISA. In the immunoneutralization studies, each mouse received 0.5 ml
of IL-12 specific antisera.
Primaxin I.V. (Merck, West Point, PA) was utilized in all experiments in which antibiotic treatments were administered. Primaxin contains equal proportions of imipenem and cilastatin. This antibiotic preparation was chosen, because imipenem is clinically effective in treating a wide variety of bacterial infections, including many caused by Gram-negative or Gram-positive aerobes and anaerobes. Furthermore, imipenem/cilastin is often recommended for the treatment of polymicrobial, intraabdominal infections (24).
Statistical analysis
ANOVA followed by two-tailed t testing was utilized to compare mean cytokine concentrations. Survival curves were analyzed by the log-rank test. The one-tailed Mann-Whitney test was used to compare bacterial CFU scattergrams. All calculations were performed on a Power Macintosh 7200 computer using Prism 2.0 (Graphpad Software, San Diego, CA). Significance was assigned for p values < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-12 production in CLP animals was initially examined because of
the well-documented proinflammatory properties of this cytokine and its
previously identified role in various other models of sepsis (5, 19, 25, 26, 27). Mice underwent CLP or sham surgery, and peritoneal
and plasma IL-12 concentrations were analyzed by ELISA at 6 and 24
h after surgery (Fig. 1
). IL-12 levels
were undetectable in samples from the peritoneum and plasma of
sham-operated mice at 6 and 24 h. However, animals experiencing
CLP-induced sepsis produced significant levels of immunoreactive IL-12
at both time points.
|
IL-12 immunoneutralization was utilized to elucidate a functional
role for IL-12 in the septic response. Rabbit anti-IL-12 immune
serum or preimmune serum was injected i.p. 2 h prior to CLP
surgery. This method of immunoneutralization proved to be clearly
detrimental in the context of the CLP model, as the 54% survival rate
observed in the control group (CLP mice given preimmune serum)
diminished to 25% in CLP mice receiving IL-12 antisera (Fig. 2). The detrimental effects of
anti-IL-12 treatment were most apparent in the first 48 h
after CLP, as the survival rate dropped from 60 to 25%.
|
concomitant with an increase in
IL-10 production
To examine potential mechanisms leading to increased mortality in
CLP mice treated with anti-IL-12 Abs, specific cytokine levels in
peritoneal washings and plasma were next determined (Fig. 3). No IL-12 was detected in the serum or
peritoneal washings of anti-IL-12 Ab-treated mice at 6 h after
CLP surgery, while mice treated with preimmune serum contained IL-12 in
both the serum and the peritoneum. Furthermore, at 6 h after CLP
surgery, IL-12 immunoneutralization prevented the production of
measurable amounts of IFN- in the peritoneum. This reduction in
IFN- corroborates previous findings showing that IL-12 drives
IFN- production (5). Interestingly, at 6 h after
surgery, IL-10 was strikingly elevated in both the peritoneum and serum
of CLP animals administered IL-12-specific Abs. A trend toward
increased IL-10 production with decreased IL-12 and IFN- production
was also evident at the 24-h time point (Fig. 3). By 48 h after
CLP, however, we did not observe any differences in the production of
these key regulatory cytokines (data not shown). These data suggested
that IL-12 immunoneutralization in the context of murine sepsis
abrogates IL-12 and IFN-, possibly permitting the unregulated
production of IL-10.
|
It has previously been shown that IL-10 inhibits the antimicrobial
host response (28), while IL-12 and IFN- promote innate
immunity (8, 29). Thus, this study explored the
possibility that anti-IL-12-treated CLP mice experienced an
uncontrolled bacterial infection due to a lack of IL-12 and IFN- and
a concomitant overproduction of IL-10. We specifically examined the
presence of bacteria in the peritoneum at 24 h after CLP, because
survival data (Fig. 2
) suggested that IL-12 immunoneutralization
altered CLP-induced mortality between the 24- and 48-h time points. At
24 h after CLP, mice treated with Abs to IL-12 displayed reduced
clearance of bacteria, as indicated by greater numbers of cultured CFUs
in the peritoneum (Fig. 4). Furthermore,
58% of CLP mice administered preimmune serum had no evidence of viable
bacteria in the peritoneum, whereas only 33% of CLP mice treated with
anti-IL-12 Ab appeared to have cleared all viable bacteria from the
peritoneum. These data suggested that the inability to clear bacteria
might be an important contributing factor to the increase in mortality
found in those mice administered IL-12 Abs prior to CLP.
|
We next explored the specific role of IL-12 in the CLP model by
coupling the administration of IL-12-specific Abs with a full course of
antibiotic therapy. As previously described, mice were administered
IL-12-specific antisera or preimmune serum i.p. 2 h prior to CLP
surgery, after which the mice were dosed with Primaxin (200 µg/dose)
at the time of surgery and every 8 h thereafter. In CLP mice
administered preimmune serum, the antibiotic treatment improved
survival from 46 to 66%, suggesting that Primaxin partially prevented
the detrimental effects of bacterial leakage into the peritoneum (Fig. 5). Nonetheless, IL-12 neutralization
remained deleterious in the context of antibiotic therapy, as the
survival rate decreased below 50% in CLP mice treated with both
anti-IL-12 serum and antibiotics. These results suggested that the
role of IL-12 during CLP-induced sepsis may extend beyond the
activation of the innate immune response.
|
To examine why IL-12 neutralization continued to be detrimental in
the context of antibiotic treatment, Gram stains were performed on
cytospins from peritoneal lavages of CLP mice treated with antibiotics
and anti-IL-12 or preimmune serum. At 4 days after CLP surgery,
bacteria were present in peritoneal fluids from mice administered both
IL-12 antisera and antibiotics (Fig. 6B). In contrast, Gram stains
of peritoneal fluids from control mice receiving preimmune serum and
antibiotics revealed no evidence of bacteria (Fig. 6A). Upon
gross morphological examination of the abdominal cavities of CLP mice,
those mice administered preimmune serum and antibiotics displayed
extensive fibrotic adhesions around the cecum, whereas CLP mice given
IL-12 antisera and antibiotics showed no similar response. Furthermore,
histological examination of cross-sections of the cecum revealed the
formation of a fibrotic membrane or "pseudomembrane" on the lumen
side of the cecum in control mice treated with preimmune serum and
antibiotics, whereas this response was not evident in CLP mice treated
with IL-12 Abs (Fig. 7). This
pseudomembrane appeared to be composed of cellular debris, inflammatory
cells, and extracellular matrix. Although differences in cellular
recruitment were not directly assessed, at 4 days after CLP surgery
ELISAs revealed no differences in several important chemotactic
cytokines. However, increased levels of IFN- in the peritoneum 4
days after CLP surgery corresponded with the lack of pseudomembrane
formation in the anti-IL-12 Ab-treated mice (data not shown).
Increased IFN- production may have contributed to the delay in
pseudomembrane formation or the fibrotic response, and as a consequence
may have contributed to the increased mortality observed in CLP mice
passively immunized to IL-12 and treated with antibiotics.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
While it has previously been shown that recurring peritoneal infection
is not directly responsible for the poor outcome associated with
peritonitis (32), the manipulation of the balance between
pro- and anti-inflammatory cytokines following the
immunoneutralization of IL-12 may permit lethal bacterial colonization
of the peritoneum. An examination of cytokine concentrations
substantiated this hypothesis, as the diminished presence of
immunoreactive IL-12 resulted in decreased IFN- in favor of elevated
IL-10. Although IL-12 was classically described as an important
mediator of Th-1 phenotypic cell-mediated immune responses, recently
more diverse roles have been ascribed to this cytokine. The
contribution of IL-12 to innate immune activation appears especially
relevant in the context of an active bacterial infection, as host
responses to a gamut of intracellular and extracellular pathogens
necessitates IL-12 activity. Furthermore, monocyte-derived IL-12
production has been shown to be vital in human patients suffering from
postoperative sepsis (33). Although, IL-12 can directly
augment host innate immunity by increasing cytolytic activity of
CD8+ and NK cell populations, its most important
contribution to host defense in the CLP model may be indirect
inflammatory cell activation via up-regulation of IFN- production by
NK and T cells (5, 11, 34). As a hallmark cytokine of the
innate immune response, IFN- up-regulates HLA-DR expression, primes
macrophages for enhanced TNF and IL-1ß synthesis, and functions to
stimulate PMN and macrophage microbicidal activity. Conversely, IL-10
serves an important immunoregulatory role during an inflammatory
response by modulating potent inflammatory processes and by preventing
tissue injury and/or shock. In addition, there is well-documented
evidence for the detrimental effects of IL-10 neutralization in various
sepsis and infection models, including CLP (17, 35, 36).
It has been shown in various infection models that too much IL-10 can
detrimentally hinder host defense, in part by suppressing the
production of important activating and/or chemotactic cytokines and by
inhibiting neutrophil and macrophage phagocytic and bactericidal
activity (14, 37, 38, 39, 40, 41). The CLP model mirrors many of the
common clinical symptoms of a septic response to polymicrobial
infection. Thus, it is likely that excessive IL-10 production without a
sufficient IL-12- and IFN--mediated response may prevent disease
resolution. It appears that in the CLP model, IL-12 neutralization
effects an imbalanced cytokine profile in the peritoneal cavity,
resulting in profound, early suppression of the innate immune response
leading to increased lethality in this bacterial sepsis model.
To further determine whether bacterial colonization associated with
IL-12 neutralization increased sepsis-induced lethality, anti-IL-12
polyclonal Abs were administered, followed by antibiotic treatment. CLP
mice receiving preimmune serum or IL-12 benefited from antibiotic
therapy, yet IL-12 immunoneutralization resulted in a worse prognosis
for CLP mice treated with antibiotics. Despite aggressive antibiotic
treatments in the anti-IL-12 Ab treatment group, we explored the
possibility that the septic mice undergoing IL-12 immunoneutralization
still suffered from bacterial contamination. In order to explore this
hypothesis, mice were sacrificed at 4 days after CLP surgery. Gram
stains of peritoneal wash cytospins revealed no obvious bacterial
presence in those mice administered antibiotics in addition to
preimmune serum, whereas CLP mice treated with anti-IL-12 serum and
antibiotics showed clear evidence of bacteria in the peritoneum. This
positive identification of bacteria in the peritoneum at 4 days after
CLP suggested either 1) a persistent bacterial colonization within the
peritoneal cavity or 2) some deficiency in the containment of
intestinal microbes within the bowel. An examination of the injured
ceca suggested the latter, as CLP mice receiving preimmune serum and
antibiotic therapy displayed fibrotic encasement of the cecum, with
fibrous adhesions to other portions of the bowel. Histologic
examination of cross-sections of the damaged ceca revealed that CLP
mice undergoing antibiotic treatment had developed a protective
membrane on the lumen side of the cecum wall. In contrast, CLP mice
administered IL-12-specific Abs and antibiotics were deficient in both
the fibrotic response around the cecum and lacked evidence of
pseudomembrane formation inside the cecum wall. While inflammation of
the intestinal wall leading to fibrosis is a well-recognized response
in chronic inflammatory bowel diseases (42), the present
study suggests that the fibrotic containment of the damaged cecum is an
important protective mechanism in the acute response to CLP induced
sepsis, serving to separate the lumen and its contents from the
damaged cecum wall. These data suggest that the
immunoneutralization of IL-12 either prevented or delayed the
development of a protective barrier to the further infiltration of the
peritoneum by intestinal microbes. Without this mechanism of containing
the damaged cecum from the rest of the body, neither the bacterial
killing response of the host nor frequent antibiotic treatments quelled
the bacterial infection that appeared to contribute to the observed
lethality. While the lack of a healing or fibrotic response in the
anti-IL-12 Ab-treated mice is currently being explored, it is
postulated that the repair of the damaged cecum is analogous to wound
repair in other parts of the body. This process requires a
sequence of events that begins with inflammation and is followed by
tissue restoration and resolution (43). The early damping
of the inflammatory response by IL-12 immunoneutralization may prevent
normal progression to subsequent stages of repair. The twofold increase
in IFN- production at 96 h by CLP mice administered both IL-12
antisera and antibiotics is suggestive of prolonged inflammation,
without progress to restoration and resolution. While increased IFN-
production may be the natural effect of a continued cellular response
to uncontrolled bacterial infection, this cytokine also functions as a
potent inhibitor of wound repair and fibrotic processes
(44, 45, 46).
In the CLP model of bacterial sepsis, IL-12 function is complex, and includes the following aspects: 1) IL-12 is a vital cofactor in the innate immunity against bacteria contained in spilled fecal matter and 2) IL-12 is involved in the containment of bacteria within the damaged cecum by directly (or indirectly) stimulating the fibrotic organization of the cecum wall. Furthermore, the latter roles for IL-12 in the septic response appeared to be critical to the survival of CLP mice, as antibiotic treatment failed to spare anti-IL-12 Ab-treated mice. Treatment of sepsis in humans has proved highly ineffective in preventing mortality, possibly casting importance upon the concept of therapeutic manipulation of cytokine cascades in septic patients. Accordingly, the present study warrants additional investigation into the role of cytokine balance during sepsis, while perhaps validating a reexamination of the clinical treatment avenue of single cytokine modulation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
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 Abbreviation used in this paper: CLP, cecal ligation and puncture.
Received for publication July 27, 1998. Accepted for publication February 16, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in lipopolysaccharide-induced pathologic alterations. Am. J. Pathol. 136:49.[Abstract]
interferon. Infect. Immun. 62:4244. and IFN- are determining factors in the ability of IL-10 to protect mice from lethal endotoxemia. J. Leukocyte Biol. 55:711.[Abstract]
production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25:672.[Medline]
interferon. J. Infect. Dis. 155:574.[Medline]
-dependent shock. Infect. Immun. 65:4734.[Abstract]
by an intracellular parasite and induces resistance in T-cell deficient hosts. Proc. Natl. Acad. Sci. USA 90:6115. impairs wound healing. J. Surg. Res. 56:288.[Medline]
in bleomycin-mouse model of lung fibrosis: downregulation of TGF-ß and procollagen I and III gene expression. Exp. Lung Res. 21:791.[Medline]
This article has been cited by other articles:
|
|
 |
|
  Y. Ishida, T. Hayashi, T. Goto, A. Kimura, S. Akimoto, N. Mukaida, and T. Kondo Essential Involvement of CX3CR1-Mediated Signals in the Bactericidal Host Defense during Septic Peritonitis J. Immunol., September 15, 2008; 181(6): 4208 - 4218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Nakano, C. Nishiyama, S. Kanada, Y. Niwa, N. Shimokawa, H. Ushio, M. Nishiyama, K. Okumura, and H. Ogawa Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections Blood, June 1, 2007; 109(11): 4846 - 4855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Watanabe, M. Kubo, K. Numata, K. Takagi, H. Mizuta, S. Okada, T. Ito, and A. Matsukawa Overexpression of Suppressor of Cytokine Signaling-5 in T Cells Augments Innate Immunity during Septic Peritonitis J. Immunol., December 15, 2006; 177(12): 8650 - 8657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Moreno, J. C. Alves-Filho, T. M. Alfaya, J. S. da Silva, S. H. Ferreira, and F. Y. Liew IL-12, but Not IL-18, Is Critical to Neutrophil Activation and Resistance to Polymicrobial Sepsis Induced by Cecal Ligation and Puncture. J. Immunol., September 1, 2006; 177(5): 3218 - 3224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Franke, W. Lante, E. Kurig, L. G. Zoller, C. Weinhold, and A. Markewitz Is interferon gamma suppression after cardiac surgery caused by a decreased interleukin-12 synthesis? Ann. Thorac. Surg., July 1, 2006; 82(1): 103 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 E. R. Sherwood, C. Y. Lin, W. Tao, C. A. Hartmann, J. E. Dujon, A. J. French, and T. K. Varma {beta}2 Microglobulin Knockout Mice Are Resistant to Lethal Intraabdominal Sepsis Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1641 - 1649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Gold, M. Parsey, Y. Hoshino, S. Hoshino, A. Nolan, H. Yee, D. B. Tse, and M. D. Weiden CD40 Contributes to Lethality in Acute Sepsis: In Vivo Role for CD40 in Innate Immunity Infect. Immun., June 1, 2003; 71(6): 3521 - 3528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Qiu, E. Gribbin, K. Harrison, N. Sinha, and K. Yin Inhibition of Gamma Interferon Decreases Bacterial Load in Peritonitis by Accelerating Peritoneal Fibrin Deposition and Tissue Repair Infect. Immun., May 1, 2003; 71(5): 2766 - 2774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Scott, C. J. Godshall, and W. G. Cheadle Jaks, STATs, Cytokines, and Sepsis Clin. Vaccine Immunol., November 1, 2002; 9(6): 1153 - 1159. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. G. Schwacha, C.-S. Chung, A. Ayala, K. I. Bland, and I. H. Chaudry Cyclooxygenase 2-mediated suppression of macrophage interleukin-12 production after thermal injury Am J Physiol Cell Physiol, February 1, 2002; 282(2): C263 - C270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Echtenacher, M. A. Freudenberg, R. S. Jack, and D. N. Mannel Differences in Innate Defense Mechanisms in Endotoxemia and Polymicrobial Septic Peritonitis Infect. Immun., December 1, 2001; 69(12): 7271 - 7276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Godshall, A. B. Lentsch, J. C. Peyton, M. J. Scott, and W. G. Cheadle STAT4 Is Required for Antibacterial Defense but Enhances Mortality during Polymicrobial Sepsis Clin. Vaccine Immunol., November 1, 2001; 8(6): 1044 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Reardon, A. Sanchez, C. M. Hogaboam, and D. M. McKay Tapeworm Infection Reduces Epithelial Ion Transport Abnormalities in Murine Dextran Sulfate Sodium-Induced Colitis Infect. Immun., July 1, 2001; 69(7): 4417 - 4423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Echtenacher, K. Weigl, N. Lehn, and D. N. Mannel Tumor Necrosis Factor-Dependent Adhesions as a Major Protective Mechanism Early in Septic Peritonitis in Mice Infect. Immun., June 1, 2001; 69(6): 3550 - 3555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 T. Inada, S. Taniuchi, K. Shingu, Y. Kobayashi, J. Fujisawa, and S.-i. Nakao Propofol Depressed Neutrophil Hydrogen Peroxide Production More Than Midazolam, Whereas Adhesion Molecule Expression was Minimally Affected by both Anesthetics in Rats with Abdominal Sepsis Anesth. Analg., February 1, 2001; 92(2): 437 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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] |
