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-receptor signaling augments the LPS-stimulated increase
in serum tumor necrosis factor-
levels
1 Center for Cardiovascular Sciences, 3 Center for Cell Biology and Cancer Research, and 2 Center for Immunology and Microbial Diseases, Albany Medical College, Albany, New York 12208
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The phagocytosis of
IgG-coated erythrocytes (EIgG) has been shown to augment the bacterial
lipopolysaccharide (LPS)-stimulated increase in serum tumor necrosis
factor-
(TNF-) levels. The present study evaluated the role of
Fc
-receptor (FcR) signaling and complement activation in the
effect of EIgG on the TNF- response to LPS. The role of FcR was
determined using FcR -chain knockout mice that lack functional
FcRI and FcRIII. In wild-type animals, EIgG caused a 16-fold
augmentation of the serum TNF- response to LPS, whereas there was no
augmentation in the FcR-deficient animals. Heat-damaged erythrocytes
also augmented the TNF- response to LPS. This effect was absent in
FcR-deficient animals. An IgG antibody against heated erythrocytes
was detected in mouse serum. The complement activation caused by EIgG
had little effect on the LPS-stimulated increase in serum TNF-
levels as indicated by activation of complement with cobra venom factor
or IgM-coated erythrocytes as well as studies with C5-deficient mice.
These results indicate that FcR signaling primarily mediates the
augmented serum TNF- response to LPS caused by EIgG.
Fc receptor -chain knockout mice; sepsis; heat-damaged
erythrocytes; complement activation; C5 knockout mice; cobra venom
factor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PREVIOUS STUDIES FROM
THIS laboratory have shown that the phagocytosis of IgG-coated
erythrocytes (EIgG) alters several aspects of macrophage function. The
phagocytosis of EIgG by isolated macrophages causes a depression of
respiratory burst capacity and phagocytic function (21,
35). Phagocytosis of EIgG by macrophages in the liver and spleen
is followed by a period of depressed in vivo macrophage clearance
function (15, 18, 20, 33). This depression of clearance
function was associated with increased mortality due to
lipopolysaccharides (LPS). Because tumor necrosis factor- (TNF-) makes an important contribution to the lethal effects of LPS
(41), it was reasoned that the increase in mortality due
to LPS after EIgG phagocytosis was due, at least in part, to augmented
TNF- secretion. Indeed, Richard et al. (30) found that
the injection of EIgG caused a 10-fold augmentation of the LPS-stimulated increase in serum TNF- levels.
Immune complexes such as EIgG could have an effect on the TNF-
response to LPS by Fc-receptor (FcR) signaling and by activating complement in the blood. Several studies have shown that FcR signaling can induce the secretion of proinflammatory cytokines by
macrophages (5, 14, 16, 36). In addition, a recent study
from this laboratory has shown that macrophages attached to immobilized
IgG have an augmented TNF- response to LPS (30). Complement activation in the blood generates anaphylatoxins (C5a and
C3a) and ligands for complement receptors (CR; C3b and iC3b). C5a and
C3a have been shown to activate nuclear factor-
B (NF-B) and
augment LPS-stimulated TNF- secretion by macrophages (4, 8,
28). In addition, signaling via macrophage CR1 and CR3 can
activate NF-B and monocytes attached to surfaces coated with the CR3
ligand, fibrinogen, had augmented LPS-stimulated TNF- secretion
(12, 40).
An area of interest of this laboratory is the potential contribution of
thermal injury-induced erythrocyte phagocytosis to the altered
macrophage function caused by this form of injury. Animal studies have
shown that thermal injury primes macrophages for an augmented TNF-
response to LPS (11, 25-27). We have proposed that
the priming of macrophages for cytokine secretion caused by thermal
injury is mediated by the increased erythrocyte phagocytosis that is
seen with this form of injury (30). This is clinically relevant because increased secretion of TNF- in burn patients contributes to the development of multiple organ failure (7, 42). In addition, the ability of immune complexes to augment the
TNF- response to LPS may be important for diseases such as rheumatoid arthritis where TNF- secretion plays a critical role in
the pathogenesis of the disease (13).
The present study examined the role of FcR signaling and complement
activation in the in vivo priming effect of EIgG on TNF- secretion. The role of FcR was investigated by using FcR
-chain knockout mice that lack functional FcRI and FcRIII.
Heat-damaged erythrocytes were used as a model of thermal
injury-induced erythrocyte phagocytosis. The role of complement
activation was determined by activating complement with cobra venom
factor (CVF) and IgM-coated erythrocytes (EIgM), both of which activate
complement without ligating FcR. In addition, C5 knockout animals
were used to determine the role of C5a in the priming effect of EIgG.
The results show that the ability of EIgG and heat-damaged erythrocytes
to augment the LPS-stimulated increase in serum TNF- levels is
absent in FcR-deficient animals and that complement activation can
prime for TNF- secretion but probably makes little contribution to the effect of EIgG.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Male mice were used for all experiments. Swiss-Webster, C57BL/6, and
C57BL/6 FcR -chain knockout mice were obtained from Taconic Farms,
and B10-D2 and B10-D2 C5-deficient mice were from Jackson Labs. Animals
were anesthetized with halothane for all procedures. All experiments
were carried out in accordance with the National Institutes of Health
Guide for the Care and Use of Laboratory Animals, and the
protocols were approved by the Institutional Review Board for the care
and use of laboratory animals at Albany Medical College.
Preparation of EIgG, EIgM, and heated erythrocytes. EIgG were prepared by incubating washed mouse erythrocytes with the IgG fraction of rabbit anti-mouse erythrocyte serum (Inter-cell Technologies) at a 1:10 dilution for 1 h. The EIgG erythrocytes were washed and injected at a dose of 2 × 1010/kg. Mouse erythrocytes that were incubated at 37°C for 1 h without IgG were also injected at a dose of 2 × 1010/kg. Controls received PBS (EIgG diluent).
IgM-coated mouse erythrocytes (EIgM) were prepared by incubating washed mouse erythrocytes with the IgM fraction of rabbit anti-mouse erythrocyte serum (Accurate) at a dilution of 1:10 for 1 h. The EIgM erythrocytes were washed and injected at a dose of 2 × 1010/kg. Heat-damaged mouse erythrocytes (heated erythrocytes) were prepared by incubating mouse erythrocytes (5 × 109/ml) at 50°C for 15 min (33). These erythrocytes were washed and injected intravenously at a dose of 5 × 1010/kg. The heated erythrocytes were spherocytes but did not lyse during heating or subsequent washing.Experimental protocol.
Animals were injected intravenously with EIgG, heated erythrocytes, or
EIgM (2 × 1010/kg) or an equal volume of PBS. LPS
(Salmonella enteriditis, 2 mg/kg, Difco Labs) was injected
intraperitoneally 2 h after erythrocyte injection, and serum
samples were collected 2 h after LPS for TNF- analysis. For
erythrocyte localization studies, erythrocytes were labeled with
51Cr, and radioactivity in the liver and spleen was
determined at the end of the experiment (2 h after LPS). The liver was
perfused via the portal vein with 8 ml of warm PBS before removal.
analysis. The
extent of complement activation was assessed from serum C3 levels as
previously described (30).
Antibody ELISA. IgG antibodies against heated erythrocytes were detected by ELISA essentially as described (2, 3). Briefly, microtiter plates (Nalge Nunc International) were coated overnight with 10 ug/ml poly-L-lysine, washed, and erythrocytes or heated erythrocytes (1 × l05/well) were allowed to adhere overnight (4°C). After being washed, the wells were blocked for 1 h at room temperature with PBS containing 5% FCS (HyClone Labs) and 0.1% Brij-35 (Sigma). Serial dilutions of mouse serum were incubated for 4 h at room temperature, the wells were washed, and goat anti-mouse IgG conjugated to alkaline phosphatase (Sigma) was incubated overnight at 4°C. Color was developed with p-nitrophenyl phosphatase substrate and read at 405 nm with an ELISA microplate reader.
TNF- ELISA.
The assay described by Richard et al. (30) was used.
Briefly, the capture antibody was a monoclonal hamster anti-murine TNF- (1 µg/ml) antibody. Standards and samples were incubated overnight, and the secondary antibody was a polyclonal rabbit anti-murine TNF-. Horseradish peroxidase-conjugated goat anti-rabbit IgG was then added. Recombinant murine TNF- was used for standards.
Statistics. Data are expressed as means ± SE. Comparisons were analyzed using ANOVA plus Newman-Keuls post hoc test for differences between groups. The level of confidence was placed at 95% for all experiments.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of EIgG on the LPS-stimulated increase in serum TNF-
levels.
To take advantage of knockout mice with specific deficiencies to study
the mechanism for the effect of EIgG on the TNF- response to LPS, it
was first necessary to establish optimal conditions for such studies in
mice. Our previous work with rats demonstrated that the prior injection
of EIgG caused about a 10-fold augmentation of the LPS-stimulated
increase in serum TNF- levels (30). Initial studies
evaluated the effect of EIgG on the time course of changes in the
LPS-stimulated increase in serum TNF- levels in mice and determined
the duration of the effect of EIgG on the TNF- response to LPS. The
time course of TNF- changes was determined by studying separate
groups of animals at 1, 2, and 3 h after the intraperitoneal injection of LPS. In animals that received PBS (intravenously), LPS (2 mg/kg) caused a characteristic large increase in serum TNF- levels
that peaked at 2 h (730 ± 140 pg/ml) (Fig.
1). The injection of EIgG (2 × 1010/kg) 2 h before LPS caused an augmentation of the
LPS-stimulated increase in serum TNF- levels (Fig. 1). The
augmentation was 12-fold at 1 h, 10-fold at 2 h, and 5-fold
at 3 h after LPS. The injection of the same dose of erythrocytes
not coated with IgG caused no change in the TNF- response to LPS
(data not shown). The duration of the effect of EIgG on the
LPS-stimulated increase in serum TNF- levels was determined by
injecting LPS at different times after EIgG. The augmentation of
TNF- levels was greatest (11-fold) when LPS was given 2 h after
EIgG (Fig. 2). EIgG caused a threefold
augmentation when LPS was given at 30 min after EIgG, and the
augmentation was still substantial (7-fold) at 6 h after EIgG. The
TNF- response to LPS had returned to control levels by 24 h
after EIgG. For subsequent studies, serum samples were taken at 2 h after LPS, and LPS was given 2 h after EIgG. Serum TNF-
levels were undetectable in animals that received EIgG only (data not
shown).
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Role of FcR in the effect of EIgG on the LPS-stimulated increase
in serum TNF- levels.
FcR -chain knockout animals were used to study the role of FcR
signaling induced by EIgG phagocytosis in the augmentation of the serum
TNF- response to LPS. The wild-type animals responded to EIgG with a
16-fold augmentation of the LPS-stimulated increase in serum TNF-
levels (Fig. 3). In contrast, EIgG did
not cause a significant augmentation of serum TNF- levels in FcR
-chain knockout animals. These results indicate that FcR is
critical for the ability of EIgG to augment the TNF- response to LPS
in vivo.
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levels in FcR -chain knockout animals was associated with
low localization of EIgG in the liver and spleen. Liver localization of
EIgG was 24.9 ± 5.6% of the injected dose in wild-type animals and was 7.1 ± 0.1% in the FcR -chain knockout animals. Liver localization of erythrocytes not coated with IgG in wild-type animals
was 5.5 ± 0.3%. Similarly, splenic localization of EIgG was
21.0 ± 1.2% in wild-type animals and 7.8 ± 0.9% in the
knockouts. Splenic localization of erythrocytes in wild-type animals
was 4.2 ± 0.3%. Thus liver and spleen localization of EIgG in
FcR knockout animals was only slightly greater than that of
erythrocytes in wild-type animals.
Effect of heat-damaged erythrocytes on the LPS-stimulated increase
in serum TNF- levels.
It is known that thermal injury causes the phagocytosis of erythrocytes
and primes macrophages for LPS-stimulated TNF- secretion (11,
15, 25-27, 29, 33). Heated erythrocytes were used as a
model for thermal injury-induced erythrocyte phagocytosis. The prior
injection of heated erythrocytes caused a 6.2-fold augmentation of the
LPS-stimulated increase in serum TNF- levels (Fig.
4). The localization of heated
erythrocytes in the liver and spleen was 25.9 ± 5.0 and 19.3 ± 2.6% of the injected dose, respectively. These results show that
heated erythrocytes can prime for TNF- secretion and suggest that
the thermal injury-induced erythrocytes phagocytosis may contribute to
the priming of macrophages for cytokine secretion.
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-chain knockout animals were studied to determine the role of
FcR in the ability of heated erythrocytes to augment the LPS-stimulated increase in serum TNF- levels. Heated erythrocytes did not cause a significant augmentation of the TNF- response to LPS
in FcR -chain knockout animals (Fig. 4). Thus FcR signaling may
mediate the priming effect of heated erythrocytes.
The role of FcR in the priming for TNF- secretion caused by
heated erythrocytes suggests that the phagocytosis of these erythrocytes was mediated by IgG. Indeed, it was found that more IgG
bound to heated erythrocytes than to erythrocytes (Fig.
5). Although the increase in IgG binding
was relatively small, a consistent two- to threefold greater IgG
binding to heated erythrocytes was seen in three experiments. This
observation is consistent with the presence of an IgG antibody against
heated erythrocytes in normal mouse serum. The presence of such an
antibody further supports the conclusion that FcR signaling mediates
the priming for TNF- secretion by heated erythrocytes.
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Role of complement activation in the effect of EIgG on the
LPS-stimulated increase in serum TNF- levels.
The ability of EIgG to activate complement in the blood may contribute
to the augmentation of serum TNF- levels. CVF was used to determine
the effect of complement activation on the LPS-stimulated increase in
serum TNF- levels. CVF activates complement via the alternative
pathway and will not result in ligation of FcR. The injection of CVF
at doses of 2 or 20 U/kg caused a 2.8- and 8.9-fold augmentation of the
LPS-stimulated increase in serum TNF- levels, respectively (Fig.
6). The 0.2-U/kg dose of CVF did not
change the TNF- response to LPS. CVF caused a dose-dependent
decrease in serum C3 levels with the lowest dose causing a 10.2 ± 1.8% decrease (Fig. 6). By comparison, EIgG caused a 6.8 ± 2.2%
decrease in serum C3 levels. LPS alone did not change the serum C3
levels (data not shown). These results indicate that complement
activation can augment the serum TNF- response to LPS, but the
extent of activation caused by EIgG was probably insufficient to
contribute to the priming effect of EIgG.
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secretion. EIgG
caused a 7.3-fold augmentation of the LPS-stimulated increase in serum
TNF- levels in the wild-type animals (Fig. 7). A similar level of augmentation was
seen in the C5-deficient animals. These results show that the level to
which EIgG induce the formation of C5a or the membrane attack complex
does not play an important role in the augmentation of the TNF-
response to LPS.
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R ligation
induced by EIgG. EIgM activate complement in the blood, become coated
with C3b/C3bi, bind to CRs on Kupffer cells, but do not interact with
FcR. Initial organ-localization studies with EIgM demonstrated that
liver localization decreased 50% between 7 min and 2 h after
injection (data not shown). This is consistent with the binding of EIgM
to CRs on Kupffer cells followed by release as the C3b/C3bi is degraded
(18, 34). Liver localization of EIgM was 12.7 ± 1.5% of the injected dose 2 h after LPS. Liver uptake of
erythrocytes was 7.1 ± 0.1%. Splenic uptake of EIgM (4.1 ± 0.6%) was not different from erythrocyte localization (4.2 ± 0.3%).
EIgM did not cause a significant augmentation of the LPS-stimulated
increase in serum TNF- levels (Fig.
8). In this experiment, EIgG caused a
7.6-fold augmentation of the TNF- response to LPS. Thus ligation of
CRs and liver uptake of EIgM did not contribute the priming effect of
EIgG. These findings are consistent with a primary role for FcR in
the ability EIgG to augment the LPS-stimulated increase in serum
TNF- levels.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
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The results presented in this paper show that FcR signaling
plays an important role in the ability of EIgG to augment the LPS-stimulated increase in serum TNF- levels. This was established from the finding that the priming effect of EIgG was absent in FcR
-chain knockout mice. The primary role of FcR signaling was
further demonstrated from studies showing that the complement activation caused by EIgG had little effect on the LPS-stimulated increase in serum TNF- levels. Complement activation with CVF and
EIgM as well as the effect of EIgG in C5 knockout mice all indicate
that complement activation due to EIgG has a weak effect on priming for
TNF- secretion.
Initial studies established that the prior injection of EIgG caused
about a 10-fold augmentation of the LPS-stimulated increase in serum
TNF- levels. These results are similar to those recently reported by
Richard et al. (30) and an earlier study by Satoh et al.
(32). In vitro studies have also shown that FcR
signaling augments the TNF- response to LPS in macrophages and that
this effect is associated with an increase in TNF- mRNA levels
(31). Other in vitro studies have shown that FcR
signaling in macrophages augments LPS-stimulated interleukin (IL)-10
secretion while inhibiting the IL-12 response (6, 37, 38).
Sutterwala et al. (38) suggested that FcR signaling may
reverse the proinflammatory response to LPS, however, our results with
TNF- indicate that FcR signaling may have a complex effect on the
balance of pro- and anti-inflammatory cytokines secreted by macrophages
stimulated with LPS.
The ability of EIgG to augment the LPS-stimulated increase in serum
TNF- levels observed in mice was similar to that seen in rats
(30). Organ localization of EIgG in mice was also similar to that previously seen in rats (18, 19). Electron
microscopy of rat tissues established that the localization of EIgG in
the liver represented phagocytosis by Kupffer cells with very few noningested EIgG detected in the liver (19). The
establishment of a mouse model for these studies in our laboratory
provided the basis for using mice with specific deficiencies to study
the mechanism of the EIgG priming for TNF- secretion.
EIgG did not augment the serum TNF- response to LPS in FcR -chain
knockout animals. This finding indicates that signaling via FcRI
and/or FcRIII is capable of augmenting the LPS-stimulated increase
in serum TNF- levels. Further studies are required to identify which
FcR mediates the priming effect. The low liver and spleen
localization of EIgG in the knockout animals indicates that there was
little phagocytosis of EIgG in these animals. This is consistent with
the work by Clynes and Ravetch (9). FcR -chain knockout
animals express FcRII receptors, but because mice express only an
inhibitory FcRII and the human FcRIIB does not mediate
phagocytosis (1), it is not surprising that EIgG phagocytosis in FcR -chain knockout animals is low.
We have proposed that the erythrocyte phagocytosis caused by thermal
injury plays a role in the priming of macrophages for cytokine
secretion that is seen with this form of injury (30). This
hypothesis is based on four lines of evidence. First, thermal injury
causes the phagocytosis of erythrocytes by macrophages in the liver and
spleen (15, 29, 33). Second, thermal injury primes
macrophages for TNF- secretion (11, 25-27). Third,
the phagocytosis of EIgG primes macrophages for an augmented TNF- response to LPS (30). Fourth, the number of EIgG required
to be phagocytosed to augment the serum TNF- response to LPS is similar to the number of erythrocytes ingested following thermal injury
in rats (18, 19, 30).
Heat-damaged erythrocytes were employed as a model for thermal
injury-induced erythrocyte phagocytosis. Heated erythrocytes are taken
up by the liver and spleen and have been shown to cause an increased
mortality due to LPS in rats (33). Accordingly, the
present study found that heated erythrocytes augmented the serum
TNF- response to LPS. In addition, the priming effect of heated
erythrocytes was absent in FcR -chain knockout animals. The presence
of an IgG antibody against heated erythrocytes in normal mouse serum
suggests that these erythrocytes become coated with IgG in the blood
and that FcRI and/or FcRIII mediate the priming for TNF-
secretion induced by heated erythrocytes. This antibody may be similar
to the natural IgG antibody against oxidatively stressed erythrocytes
described by Lutz et al. (23). Complement components and
phosphatidylserine on the surface may have contributed to the clearance
of the heated erythrocytes (17, 23, 24). These results
indicate that heated erythrocytes can prime for TNF- secretion and
suggest that thermal injury-induced erythrocyte phagocytosis may
contribute to the macrophage priming induced by this form of injury.
Injection of EIgG causes activation of complement. The possibility that
this complement activation contributed to the augmented TNF-
response to LPS caused by EIgG is based on the observations that C5a
and ligation of CR1 and CR3 can activate NF-kB and prime macrophages
for LPS-stimulated TNF- secretion (4, 8, 12, 28, 40).
However, it was found that high doses of CVF were required for priming,
C5-deficient mice had normal priming with EIgG, and EIgM did not prime,
suggesting that complement activation plays only a minor role in the
priming due to EIgG.
CVF causes complement activation via the alternative complement pathway
in the fluid phase. Activation of complement in this way results in the
generation of C5a without depositing significant concentrations of
C3b/iC3b on erythrocytes or other cell surfaces. The higher
doses of CVF augmented the LPS-stimulated increase in serum TNF-
levels, indicating that activation of complement alone can prime for
TNF- secretion. However, the extent of complement activation
required to prime for TNF- secretion exceeds that caused by EIgG
because the lowest dose of CVF did not augment the TNF- response to
LPS but depleted C3 levels to the same extent as EIgG.
The role of C5 in the EIgG priming for TNF- secretion was determined
using mice that lacked this complement component. C5 knockout mice had
a normal augmentation of the TNF- response to LPS caused by EIgG.
Thus the amount of C5a generated by EIgG in wild-type animals did not
contribute to the priming for TNF- secretion.
EIgM were used to determine the role of CR ligation in the priming
effect of EIgG. EIgM activate complement, become coated with C3b/iC3b,
bind CR on macrophages, but do not ligate FcR (18, 34).
After an intravenous injection is given, EIgM bind to Kupffer cells,
but because CRs are not highly phagocytic, some of the EIgM return to
the blood as the complement components are degraded. It was found that
EIgM did not augment the LPS-stimulated increase in serum TNF-
levels. Thus the degree of CR ligation and complement activation caused
by EIgM was insufficient to augment the TNF- response to LPS.
Perspectives
The present study has shown that FcR signaling augments the
LPS-stimulated increase in serum TNF- levels. The ability of FcR
signaling to augment the TNF- response to LPS may be relevant to
diseases in which immune complexes could augment cytokine secretion in
response to an infection and thereby initiate or exacerbate the
condition. With atherosclerosis, immune complexes formed with antibodies against oxidized low-density lipoproteins may prime macrophages for an exaggerated response to infections with
Chlamydia pneumoniae (10, 22). For arthritis,
autoantibodies may prime synovial macrophages for infections that could
initiate or exacerbate the condition (13, 39). Thus the
combination of immune complex-induced FcR signaling and bacterial
products may act synergistically to augment cytokine secretion. It was
also found that heat-damaged erythrocytes were able to augment the
TNF- response to LPS in an FcR-dependent manner. This observation
suggests that thermal injury-induced erythrocyte phagocytosis may prime
macrophages for an exaggerated inflammatory response to sepsis or
endotoxemia. Indeed, several studies have shown that macrophages
removed from animals after thermal injury are primed for LPS-stimulated
cytokine secretion (11, 25-27). An exaggerated
inflammatory response is considered to contribute to the development of
multiple organ dysfunction in burn patients (7, 42).
Further studies are required to determine the effect of FcR
signaling on the secretion of proinflammatory cytokines other than
TNF- as well as on the balance of pro- and anti-inflammatory
cytokine secretion stimulated by LPS or sepsis.
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ACKNOWLEDGEMENTS |
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The authors thank W. Hobb for secretarial assistance.
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FOOTNOTES |
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This study was supported by grants from National Institutes of Health (GM-50368, AI-41715, and HL-62120) and the New York State Affiliate of the American Heart Association (50893T).
Address for reprint requests and other correspondence: D. J. Loegering, Center for Cardiovascular Sciences, Mail Code 8, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208 (E-mail: loegerd{at}mail.amc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 30 June 2000; accepted in final form 5 December 2000.
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METHODS
RESULTS
DISCUSSION
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