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* Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 and
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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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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2, 26-kDa protein, B cell stimulatory factor-2,
hybridoma/plasmocytoma growth factor, hepatocyte stimulating factor,
monocyte granulocyte inducer-2, cytotoxic T cell differentiation
factor, and thrombopoietin (2). IL-6 facilitates its
effects through a specific 80-kDa receptor (3) together
with the membrane gp130, which is required for intracellular signal
transduction (4, 5). IL-6 has been described as a cytokine
with proinflammatory and anti-inflammatory effects, one important
feature being the ability to induce production of acute phase proteins
in the liver (6, 7). Although IL-6 does not appear to
significantly influence serum levels of TNF-
and IL-8 or induce
neutrophil degranulation in a model of endotoxemia in chimpanzees
(8), its serum levels are reported to be influenced by
TNF- and IL-1 in humans (9, 10). It has been known
since 1989 that IL-6 is greatly up-regulated in the serum of patients
with bacterial infection or sepsis (11, 12, 13). Many studies
have reported a positive correlation between IL-6 serum levels and
outcomes in septic patients (14, 15, 16, 17). The impact of IL-6
on the outcome in experimental sepsis is controversial. It has been
reported that injections of recombinant IL-6, even in high doses, had
no harmful effects in otherwise normal dogs (18). Several
studies have demonstrated beneficial effects of blocking Abs to IL-6
when used in models of TNF- or Escherichia coli challenge
in mice (19). The underlying mechanism of such beneficial
effects has not been defined. It is known that other serum cytokine
levels do not seem to be altered during IL-6 blockade. There is strong evidence that, in the early phases of sepsis, the complement activation product, C5a, plays a harmful role in rodents following cecal ligation/puncture (CLP)4 or infusion of LPS (20, 21, 22, 23, 24). This adverse outcome had been linked to a C5a-dependent loss of the respiratory burst (H2O2 production) in blood neutrophils from septic rats. The responses to C5a are mediated by a pertussis toxin-sensitive G protein-linked seven transmembrane-spanning C5aR, which belongs to the superfamily of rhodopsin-type receptors (25, 26). We recently found that this receptor is strongly up-regulated in various organs during the onset of sepsis in mice and that its blockade results in greatly improved survival in CLP mice (27). In liver, IL-6 has been reported to up-regulate mRNA expression for C5aR (28). We have found that IL-6 strongly up-regulates C5aR on rat lung epithelial cells, thymocytes, and endothelial cells (29, 30).
The goal of the current study was to investigate effects of IL-6 blockade during the onset of sepsis in mice and to assess the linkage between IL-6 and regulation of C5aR during CLP-induced sepsis. We demonstrate for the first time that IL-6 blockade during CLP-induced sepsis in mice results in a significantly reduced induction of C5aR in lung, liver, kidney, and heart, leading to greatly improved survival.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Unless otherwise specified, reagents were obtained from Sigma-Aldrich (St. Louis, MO). Specific monoclonal rat anti-mouse IL-6 Ab (anti-IL-6) was obtained from BD PharMingen (San Diego, CA). This Ab was characterized by the manufacturer as specifically neutralizing of recombinant mouse IL-6 (references provided by BD PharMingen), with a neutralizing activity of >95% when used in a concentration between 0.5 and 2.0 µg/ml.
Peptide synthesis and production of anti-mouse C5aR Abs
A 37-aa peptide spanning the N terminus of the mouse C5aR (MDPIDNSSFEINYDHYGTMDPNIPADGIHLPKRQPGDC) was synthesized using an Applied Biosystem 430A peptide synthesizer (Foster City, CA), as described elsewhere (31). The peptide was then coupled to keyhole limpet hemocyanin by the glutaraldehyde method and used for the immunization of rabbits. The anti-peptide specific Ab was purified by affinity chromatography using the synthetic peptide coupled to cyanogen bromide-activated Sepharose 4B (Amersham Pharmacia Biotech, Piscataway, NJ).
Quantitation of IL-6 by ELISA
IL-6 serum levels were determined using ELISA kits (BioSource International, Camarillo, CA) according to the manufacturer’s instructions. Approximately 500–800 µl blood were drawn from healthy control animals and from animals at various time points after CLP. The blood samples were placed on ice and allowed to clot before centrifugation at 3000 x g for 10 min. Serum samples were then used in various dilutions for ELISA performance.
Experimental sepsis induced by CLP and organ preparation
Seven- to 8-wk-old specific pathogen-free male B10/D2 nsnJ mice
(The Jackson Laboratory, Bar Harbor, ME) were used in all studies.
Anesthesia was achieved by i.p. injection of a
ketamine/xylozine/Dulbecco’s PBS (DPBS) solution (11 µl/g
body weight; 1 ml of ketamine containing 9% xylozine was diluted with
7 ml of DPBS). In the CLP model, approximately two-thirds of the cecum
was ligated, using a 1.5-cm abdominal midline surgical incision. The
ligated part of the cecum was punctured through and through with a
21-gauge needle. After repositioning of the bowel, the abdomen was
closed in layers using a 4.0 surgical suture (Ethicon, Somerville, NJ)
and metallic clips. Sham animals underwent the same procedure without
ligation or puncture of the cecum. For animal sacrifice, the inferior
vena cava was incised and 
600 µl of blood withdrawn. The chest was
then opened and the pulmonary artery was slowly perfused with 40 ml of
DPBS, with perfusion liquid leaking out of the open caval vein after
perfusion of the arterial system. Perfusion quality was optically
controlled by observing the organ color change (to white) as the blood
was completely removed. Immunohistochemical staining experiments for
mouse neutrophils were conducted for organs of CLP animals to assure
the complete removal of neutrophils from the vessels and endothelium
with the above-mentioned flushing method. Organs were removed for
radioactivity analysis or snap frozen for RT-PCR experiments and
immunohistochemical staining. In lungs, bronchoalveolar lavage was also
performed with a total volume of 3 ml.
In vivo binding studies
Polyclonal rabbit anti-mouse C5aR IgG (affinity purified using the N-terminal peptide) or normal rabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA) was labeled with 125I, using the chloramine method, as described elsewhere (32). This protocol involves gentle oxidation. Immediately after CLP, animals received anti-IL-6 (1.33 mg/kg body weight) or control IgG in 200 µl of DPBS via injection into the penile vein. For the binding studies animals were sacrificed 6 and 12 h thereafter. Organ radioactivity was compared with that in CLP animals sacrificed at 0 h. 125I-labeled anti-mouse C5aR IgG (100 ng) together with 2 µg nonlabeled Ab as carrier in a total volume of 200 µl of DPBS was administered i.v. 15 min before sacrificing the animals. Blood was withdrawn from the abdominal caval vein to determine the amount of radioactivity in the blood 15 min after injection of 125I-labeled anti-C5aR IgG. Organs were then thoroughly flushed with DPBS and then harvested (as described above) and weighed. Radioactivity was measured in a gamma counter (1261 Multi; Wallac, Gaithersburg, MD). Data were expressed as cpm per gram of tissue, divided by the cpm in 100-µl blood sample for each individual animal.
RNA isolation and detection of C5aR mRNA by semiquantitative RT-PCR
Organs from mice were obtained 0, 3, 6, and 12 h after induction of CLP and prepared as described above. Total RNA was isolated with the TRIzol method (Life Technologies, Rockville, MD) according to the manufacturer’s instructions. Digestion of any contaminating DNA was achieved by treatment of samples with RQ1 RNase-free DNase (Promega, Madison, WI).
Reverse transcription was performed with 5 µg of RNA using the Superscript II RNase H- Reverse Transcriptase (Life Technologies) according to the manufacturer’s protocol. PCR was then performed with the following primers for C5aR: 5' primer, 5'-TAT AGT CCT GCC CTC GCT CAT-3', and 3' primer, 5'-TCA CCA CTT TGA GCG TCT TGG-3'. The primers were designed for a 409-bp cDNA amplification in the middle region of the rat C5aR cDNA (position 373–781). The primers for the "housekeeping" gene GAPDH were as follows: 5' primer, 5'-GCC TCG TCT CAT AGA CAA GAT G-3', and 3' primer, 5'-CAG TAG ACT CCA CGA CAT AC-3'. Thirty-five cycles were used for amplification. The RT-PCR product was confirmed by electrophoresis of samples in 1.2% agarose gel. Control experiments were performed with the samples in which reverse transcriptase was not added to rule out contaminating DNA being responsible for any results. PCR was performed using different cycle numbers for C5aR and GAPDH primers, to assure that DNA was detected within the linear part of the amplifying curves for both primers. Results are presented in a semiquantitative manner.
Statistics
Data sets were analyzed using one-way ANOVA, and individual group means were then compared with the Student-Newman-Keuls multiple comparison test. Statistical analyzes for survival studies were performed using proportional hazards modeling. In both tests, significance was considered for values of p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the efficiency of monoclonal neutralizing rat IgG Ab
(anti-IL-6) to suppress IL-6 in vivo, we investigated by ELISA
serum IL-6 levels during the onset of CLP-induced sepsis in mice. Fig. 1
demonstrates the ability of
anti-IL-6 to greatly suppress IL-6 in the serum of mice 6 h
after induction of sepsis by CLP. Reduction of detectable IL-6 was dose
dependent when compared with animals receiving irrelevant rat IgG
(IgG). Healthy control animals showed no detectable IL-6 serum levels
(<3 pg/ml). The most protective dose of anti-IL-6 (1.33 mg/kg) in
sepsis (see Fig. 2) resulted in serum IL-6 levels of 184 pg/ml
on average, which presents a significant increase when compared with
healthy control animals and a significant decrease when compared with
control IgG-injected CLP mice. The doses of 2.66 and 0.33 mg
anti-IL-6/kg body weight resulted in serum IL-6 levels of 15 and
629 pg/ml, respectively. The intermediate dose of (1.33 mg/kg)
of anti-IL-6 was used for subsequent in vivo experiments.
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To determine potential beneficial effects of anti-IL-6
treatment in sepsis, we injected various concentrations (0.33, 1.33,
and 2.66 mg/kg body weight) of anti-IL-6 i.v. in 200 µl of DPBS
at the start of CLP (time 0 h). Companion mice received normal rat
IgG (1.33 mg/kg body weight) at the time of CLP. The results of these
experiments are presented in Fig. 2
A. Anti-IL-6 treatment
resulted in significantly improved survival that was dose dependent. A
dose of 1.33 mg/kg body weight resulted in a 7-day survival of 56%,
whereas 0.33 mg/kg body weight showed a survival of 42%. Surprisingly,
the highest dose of anti-IL-6 (2.66 mg/kg body weight) resulted in
a much less improved survival, with a 7-day survival of only 18%. Each
of the anti-IL-6-treated groups was statistically significantly
different from the control group receiving an irrelevant rat IgG at
time 0. This group had no survivors by the fifth day. In the
anti-IL-6-treated groups, the survival curves showed additional
drop-offs from days 5 to 7. These results suggest that sepsis-induced
IL-6 is harmful and that there is a certain "threshold" of IL-6,
below which host defenses are compromised. Delayed infusion of the most
potent dose of anti-IL-6 (1.33 mg/kg body weight) at 4 h after
CLP resulted in no significant beneficial effects on survival, even
though 16% of the mice survived at day 7 (Fig. 2B).
Because, as pointed out in the introduction, we found that in
vitro exposure to IL-6 can induce C5aR in various tissues and cells,
and we have reported before that blockade of C5a or C5aR resulted in
greatly improved survival, we sought to investigate whether the
observed beneficial effects of anti-IL-6 treatment could be linked
to altered C5aR expression during sepsis.
Reduced binding of anti-C5aR Ab in anti-IL-6-treated CLP mice
We recently found that binding of
125I-labeled IgG Ab to mouse C5aR is
significantly increased in lung, liver, kidney, and heart during the
onset of sepsis in mice at 3, 6, and 12 h after CLP
(27). In these studies, an irrelevant
125I-labeled control IgG showed no evidence of
increased organ binding. In the current studies, we investigated the
effects of anti-IL-6 treatment on the induction of C5aR in CLP
mice. Fig. 3 summarizes the results of
these studies. Six hours after CLP, binding of
125I-labeled anti-C5aR IgG to lung, liver,
kidney, and heart was significantly increased when compared with
results from CLP mice at time 0. Treatment with 1.33 mg
anti-IL-6/kg body weight resulted in a significant suppression in
binding of Ab to C5aR in all four organs, as defined by reduced binding
of 125I-labeled anti-C5aR IgG. The observed
binding in the four anti-IL-6-treated groups 6 h after CLP was
not statistically different from the binding to organs from 0-h CLP
animals. Interestingly, by 12 h after CLP, the increase in binding
of 125I-labeled anti-C5aR to the various
organs in the control IgG-treated group had fallen back to the levels
found at 0 h following CLP (data not shown). Therefore, IL-6
appears to have a time-limited effect in CLP mice in terms of increased
levels of C5aR. The binding data suggest that C5aR induction early
after the onset of sepsis (6 h after CLP) is greatly suppressed in
lung, liver, kidney, and heart when animals were first treated with
anti-IL-6.
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To extend the results from the binding studies, we isolated total
RNA at various time points (0, 3, 6, and 12 h) after CLP from
lung, liver, kidney and heart from mice that had been treated with
irrelevant IgG Ab or with anti-IL-6 IgG and performed RT-PCR for
C5aR mRNA expression. The results of these experiments are demonstrated
in Fig. 4. Healthy control animals showed
little or no detectable expression (ctrl column) of mRNA for C5aR in
each of the organs. Three, 6, and 12 h after induction of sepsis
by CLP, a significant increase in C5aR mRNA expression was observed in
each of the four organs, peaking at 6 h after CLP. In animals
treated with anti-IL-6, increased mRNA expression for C5aR was
significantly suppressed at 3, 6, and 12 h after CLP in all four
organs when compared with CLP mice treated with normal (ctrl) IgG.
Interestingly, in liver from CLP mice treated with anti-IL-6, there
was a late increase (12 h after CLP) in C5aR mRNA expression. The
results of the RT-PCR experiments suggest that IL-6 blockade reduces
C5aR mRNA expression during the early onset of sepsis, which is
consistent with the organ binding data using
125I-labeled anti-C5aR (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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infusion) has been reported to have no protective effects in terms of
improved survival (35). Other groups have reported in
rodents the beneficial effects of anti-IL-6 in models of
Escherichia coli challenge, TNF- infusion
(19), endotoxic shock (36), and gut-derived
sepsis with Escherichia coli gavage and thermal injury
(37). In our study, we determined the effects of blockade
of mouse IL-6 with a neutralizing rat mAb in CLP mice. This CLP model
of sepsis is believed to closely simulate clinical sepsis in humans
because of the polymicrobial-driven inflammatory process. We have
demonstrated a dose-dependent beneficial effect of IL-6 blockade in
this sepsis model, using anti-IL-6 in mice. Interestingly, high
doses of anti-IL-6 (2.66 mg/kg), as well as low doses (0.3 mg/kg),
appeared to be less beneficial for the outcome in sepsis, correlating
with lower or higher detectable IL-6 levels in the serum at 6 h
after CLP (Fig. 1). This suggests that, in CLP-induced sepsis, high
levels of IL-6 are harmful and that, if Ab-induced blockade of IL-6 is
excessive, increased deaths occur, perhaps because low levels of IL-6
are beneficial for host defenses, in a manner similar to what has been
described for Ab-induced blockade of TNF- in murine sepsis
(38). As pointed out above, IL-6 is responsible for proinflammatory as well as for anti-inflammatory effects in addition to its numerous other functions, such as stimulation of cell growth. This variety of effects may be the reason why IL-6 blockade is useful in one inflammatory setting but harmful or nonbeneficial in other settings. This may be the reason for the difficulties in previously published studies that have attempted to define the biology of IL-6. We were especially interested in finding an explanation for the improved survival by investigating the influence of IL-6 blockade on the expression of C5aR during sepsis. Our recent studies have indicated that C5aR is strongly up-regulated during the onset of CLP-induced sepsis in mice in lung, liver, kidney, and heart, and that Ab-induced blockade of C5aR in CLP mice results in dramatically improved survival. In the current studies, we demonstrated that blockade of IL-6 during CLP-induced sepsis resulted in decreased elevation of C5aR mRNA and significantly reduced in vivo binding of 125I-labeled anti-C5aR IgG in lung, liver, kidney, and heart when compared with the strong increase occurring in control CLP mice 6 h after CLP and treated with normal IgG. Interestingly, in the liver we observed a late increase in C5aR mRNA 12 h after CLP in the anti-IL-6-treated animals, which was not reflected on the protein level with the binding data. This phenomenon is currently not understood, but it is possible that the regulation of C5aR mRNA production in the liver may differ from that of other organs at late stages of sepsis when IL-6 has initially been blocked.
We also investigated the possible influence of IL-6 blockade on TNF-
and MIP-2 serum levels during CLP-induced sepsis in mice, but we were
unable to detect significant differences in CLP animals treated with
either anti-IL-6 or irrelevant IgG (data not shown). It has been
reported that IL-6 does not alter serum levels of TNF- or IL-8 in an
endotoxic shock model in vivo in chimpanzees (8). Because
there is a broad variety of cytokines that may play a role during IL-6
blockade, additional mechanisms may also be involved in the improved
survival of CLP mice treated with anti-IL-6.
It has been reported that IL-6 knockout mice do not show improved
survival in CLP-induced sepsis (39) and that they suffer
from impaired immune and acute-phase responses (40). These
reports suggest that a certain amount of IL-6 production in acute
inflammation may be required for an appropriate immune response or
innate immunity. In fact, we demonstrated that the most potent dose of
anti-IL-6 (1.33 µg/kg body weight) for optimal survival was
associated with measurable IL-6 serum levels 6 h after CLP as
compared with serum from healthy control animals (Fig. 1). Although
IL-6 levels in the sera of CLP mice treated with anti-IL-6 (1.33
mg/kg) were suppressed by 90% (Fig. 1), there still remained
detectable IL-6. It is possible that this intermediate dose of
anti-IL-6 permitted a small but significant amount of IL-6 to
remain, resulting in much less up-regulation of C5aR but adequate to
facilitate other protective host-defense responses. The lower dose of
IL-6 (0.33 mg/kg) may have been inadequate to reduce IL-6 levels
sufficient to suppress up-regulation of C5aR. The paradoxical finding
that a higher dose of anti-IL-6 resulted in reduced survival (Fig. 2) may reflect that the total blockade of IL-6 results in the loss of
some beneficial effects of IL-6. The latter finding is supported by the
finding that IL-6 knockout mice also fail to show improved survival in
CLP-induced sepsis (39). The dose dependency of
anti-IL-6 for the beneficial outcome (Fig. 2) provides a possible
explanation for inconsistent findings dealing with blockade of IL-6, as
reported above. Delayed infusion of anti-IL-6 at 4 h after CLP
resulted in no significant improvement of survival, similar to the
findings with delayed anti-C5aR treatment (27),
suggesting that an early interception of C5aR up-regulation is
necessary to counteract a harmful compromising of innate immunity.
We have recently found that blockade of C5aR during CLP-induced sepsis in mice resulted in reduced serum IL-6 levels 6 h after CLP (27). In the current study, we present evidence that blockade of IL-6 during sepsis leads to a diminished increase in C5aR expression in various organs. These results suggest a complex feedback mechanism between C5a/C5aR interaction and serum IL-6 levels. Blockade of one of the two mediators ultimately leads to a reduced production of the other one. In experimental sepsis, there is evidence that both, C5a and IL-6, are produced excessively, maybe due to a positive feedback between both parameters. This could explain why interception of either one of them has been shown to be beneficial for the outcome in sepsis while simultaneously the increase of the other mediator or its receptor was diminished.
The question arises as to why increased expression of C5aR in lung, kidney, heart, and liver may be linked to worsened survival in CLP. There is no direct evidence to resolve this question. It is possible that heightened C5aR expression in these organs in CLP mice is concomitant with C5a generation in blood. This combination might result in diminished organ performance, resulting in multiorgan failure.
Taken together, our data suggest that the appropriate degree of IL-6 blockade is beneficial for the outcome in CLP-induced sepsis in mice, and this is linked to inhibition of the early increases of C5aR, in a variety of organs from CLP mice. The results of the current study suggest a functional mechanism for beneficial IL-6 blockade during the onset of sepsis. In addition, our findings suggest a potential preventive treatment, targeting IL-6 and C5a/C5aR in patients at high risk for development of sepsis. A balanced amount of IL-6 serum content during the onset of sepsis may thereby be a key for successful intervention.
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Footnotes |
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2 N.C.R. and T.A.N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Peter A. Ward, Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602. E-mail address: pward{at}umich.edu
4 Abbreviations used in this paper: CLP, cecal ligation/puncture; DPBS, Dulbecco’s PBS.
Received for publication July 17, 2002. Accepted for publication October 21, 2002.
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References |
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2) receptor. Science 241:825.2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc. Natl. Acad. Sci. USA 84:7251. and interleukin 1 induce interleukin 6 production in vivo. Clin. Immunol. Immunopathol. 53:488.[Medline]
2/IL-6 in serum and body fluids during acute bacterial infection. J. Immunol. 142:948.[Abstract]
challenge in mice. J. Immunol. 145:4185.[Abstract]
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