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R1
* Department of Veterans Affairs Medical Center, Albuquerque, NM 87108; Departments of
Internal Medicine and
Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIb, and to
the -chain-associated receptor, FcRI. The goal ofthis
study was to determine whether FcRs are necessary for the protective
effect of CRP. The ability of CRP to protect mice from a lethal dose of
LPS was confirmed using injections of 500 and 250 µg of CRP at 0 and
12 h. CRP treatment of FcRIIb-deficient mice increased
mortality after LPS challenge and increased serum levels of TNF and
IL-12 in response to LPS. CRP did not protect FcR -chain-deficient
mice from LPS-induced mortality. Treatment of normal mice, but not
-chain-deficient mice, with CRP increased IL-10 levels following LPS
injection. In vitro, in the presence of LPS, CRP enhanced IL-10
synthesis and inhibited IL-12 synthesis by bone marrow macrophages from
normal, but not -chain-deficient mice. The protective effect of CRP
appears to be mediated by binding to FcRI and FcRII resulting in
enhanced secretion of the anti-inflammatory cytokine IL-10 and the
down-regulation of IL-12. These results suggest that CRP can alter the
cytokine profile of mouse macrophages by acting through FcR leading
to a down-regulation of the inflammatory
response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rs on phagocytic cells to mediate phagocytosis
(7, 8).
CRP has been shown to have both proinflammatory and
anti-inflammatory effects in vitro and in vivo. In vitro, CRP
induced the production of IL-1 and TNF by human monocytes and mouse
macrophages (9, 10, 11). However, CRP and other acute phase
proteins also enhanced production of IL-1RA in human PBMCs (12, 13). Injection of CRP increased myocardial injury in an
ischemia-reperfusion model that was dependent on C activation
(14). In other studies, elevated levels of CRP appeared to
be anti-inflammatory, decreasing alveolitis in response to
chemotactic factors (15). High concentrations of CRP also
inhibited neutrophil chemotaxis in vitro (16). The ability
of CRP to protect mice from lethal challenge with LPS has been
demonstrated in mice rendered transgenic for rabbit CRP
(17) and in mice given human CRP by injection
(18). To our knowledge, the ability of mice expressing
human CRP as a transgene to resist LPS challenge has not been tested.
These apparent discrepancies in the effect of CRP on the inflammatory
response may be due to differential engagement of proinflammatory and
anti-inflammatory FcR and activation of C.
The FcR family is composed of three major groups, FcRI, FcRII,
and FcRIII (19). FcRI is the high-affinity receptor
for IgG and along with FcRIII induces activating signals in response
to cross-linking. In the mouse, FcRII is a low-affinity receptor for
IgG that delivers a regulatory signal to leukocytes (20).
CRP binding to the activating receptor FcRI and the regulatory
receptor FcRII has been demonstrated (21). The balance
between activation of these two receptors may explain the pro- and
anti-inflammatory properties of CRP.
Although the use of human CRP in the mouse is somewhat artificial, this
model has proven useful in a number of studies of CRP function
(22, 23, 24). By passively administering CRP into mice that
express only low levels of mouse CRP, the timing and concentration of
the CRP can be experimentally manipulated. The FcR interactions appear
to be quite similar between man and mouse in that CRP binds to FcRI
and FcRII in both man and mouse. In both cases functional studies
have failed to show an interaction between FcRIII and CRP. Because
FcRII in the mouse is present only in inhibitory forms (FcRIIb,
containing immunoreceptor tyrosine-based inhibitory motifs), this
simplifies the interpretation of the results using
FcRII-deficient mice.
In the current study, the effect of CRP on a strong inflammatory
stimulus was examined. Under these conditions, CRP has a clear
anti-inflammatory activity that protects mice from lethality due to
LPS challenge. Although the ability of CRP to protect from LPS was
discovered >8 years ago, the mechanism remains unknown
(25). In transgenic mice, induction of CRP synthesis by
diet increased resistance to lethality from LPS, platelet-activating
factor, TNF plus IL-1, and galactosamine plus LPS but not TNF alone
(17). The recent finding that CRP interacts with cells
through FcR suggests a possible mechanism for CRP-mediated
protection (8, 21, 26). It has been demonstrated that IgG
complexes or IgG-coated E can induce the production of the
anti-inflammatory cytokine, IL-10, and decrease the production of
the proinflammatory cytokine, IL-12 (27). It was further
demonstrated that macrophages preincubated with a low dose of LPS and
E-IgG could protect mice from endotoxin challenge (28).
Therefore, we postulated that CRP might act in a manner similar to IgG
to limit inflammation during the acute phase response.
In these studies, the ability of CRP to protect mice from lethal LPS
challenge was reexamined in normal mice and in mice deficient in
different FcR. Specifically, the effect of CRP on the survival of
mice deficient in either FcR -chain or in FcRIIb challenged with
a lethal dose of LPS was measured. The levels of TNF, IL-10, and IL-12
were measured in the blood of LPS-challenged mice. The effect of human
CRP administration on these cytokines was compared with the survival of
LPS-challenged mice treated with CRP. The results suggest that the
administration of human CRP leads to an alteration in the balance of
pro- and anti-inflammatory cytokines, which alters survival of mice
exposed to an inflammatory stimulus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human CRP was purified from pleural fluid by affinity, gel filtration, and ion exchange chromatography as previously described (29). The purity of the CRP preparations was determined by 12.5% SDS-PAGE on overloaded and normal samples. The gels were stained with a sensitive silver stain. No bands other than the major 25-kDa CRP band were seen. Specifically, no contamination by IgG was seen. Endotoxin was removed from CRP by passage over an ActiClean Etox column (Sterogene Bioseparations, Carlsbad, CA). Endotoxin levels were <0.1 ng/mg protein as measured by a chromogenic Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD). LPS (Escherichia coli O127:B8 no. L3129 and O55:B5 no. L2880 (prepared by phenol extraction)) were purchased from Sigma-Aldrich (St. Louis, MO).
Mice
Male C57BL/6Ncr mice were purchased from the National Cancer
Institute (Frederick, MD). FcRIIb-deficient mice (30)
and FcR -chain-deficient mice (31) on a C57BL/6 x
129 background were bred at the Veterans Affairs Veterinary Medical
Unit (Albuquerque, NM) from breeder pairs purchased from The Jackson
Laboratory (Bar Harbor, ME). The -chain-deficient mice do not
express functional FcRI, FcRIII, or Fc
RI. The
FcRIIb-deficient mice lack individual receptor expression only. Both
male and female FcR-deficient mice were used. All mice were housed
conventionally and were used between 7 and 14 wk of age. All
experimental procedures involving animals were approved by the
Institutional Review Board of the Department of Veterans Affairs
Medical Center (Albuquerque, NM).
Cells
Bone marrow macrophages (BMMs) were prepared as previously described (32). Briefly, mice were killed, femurs were isolated under sterile conditions, the ends of the femurs were excised, and bone marrow was flushed from the femurs in HBSS with 0.2% human serum albumin. Cells were resuspended in 12–15 ml DMEM with 2% FCS and 2% L cell-conditioned medium and allowed to adhere to tissue culture dishes for 2 h. Nonadherent cells were removed and cultured in tissue culture flasks in DMEM, 2% FCS, and 15% L cell-conditioned medium, for 7–10 days. Nonadherent cells were removed after overnight culture, and cultures were fed after 4 days. BMMs were removed from tissue culture flasks with 5 mM EDTA 12 h before use and were then grown overnight in DMEM with 10% FCS, 2 mM glutamine in 24-well plates. Macrophages were cultured at 4 x 105 cells/ml in 0.5 ml of medium per well. Supernatants were collected 8 h after addition of the stimuli.
LPS challenge
For protection against lethality, mice were challenged with 500 µg of 055:B5 LPS i.p. at time 0. Mice received i.v. injections of 500 µg of CRP at time 0 and 250 µg of CRP at 12 h. Control mice received TBS i.v. at 0 and 12 h. Mice were monitored at 6- to 12-h intervals. For cytokine assays, mice were injected with 200 µg of CRP 2 h before the injection of 50 µg of LPS. Mice were then bled at the times indicated in the legends and the serum was analyzed for the cytokines of interest.
Cytokine assays
Serum and cell culture supernatants were assayed for IL-12 p70,
IL-10, and TNF by ELISA (BD PharMingen, San Diego, CA). For LPS
stimulation of macrophages, cultures were treated with 0.1–100 ng/ml
of O127:B8 LPS. CRP-treated cells received 100 µg/ml of purified,
endotoxin-free CRP. This concentration of CRP is sufficient to provide
near saturation of binding and activation of macrophages through
FcR.
Data analysis
Graphical and statistical analyses were performed using GraphPad Prism software (GraphPad, San Diego, CA). Survival curves were plotted by the method of Kaplan and Meier and compared by the log-rank test (Mantel-Haenszel test). This analysis takes into account the time of death as well as the absolute numbers of mice surviving. Throughout the results the term "protection" indicates significantly enhanced survival. Cytokine levels were compared by t tests. Values of p < 0.05 are considered significant and are represented on graphs as *. Values of p < 0.01 are considered to be highly significant and are represented by **.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies showed that rabbit CRP expressed as a transgene
in mice could protect mice from LPS-induced mortality
(17). These investigators could not reproduce this effect
using passively administered CRP. However, others reported that human
CRP could provide protection from LPS when given at higher doses
(18). Other studies have shown that CRP is also protective
from LPS from Vibrio vulnificus (33). To
confirm that passive administration of human CRP can protect mice from
challenge with a lethal dose of LPS, C57BL/6 mice were challenged with
500 µg of LPS at time 0. One group of mice received 500 µg of CRP
at time 0. A second group received 500 µg of CRP at time 0 and 250
µg of CRP at 12 h. The third group of mice received saline at 0
and 12 h. Survival was followed for 7 days. Mice receiving CRP
using either protocol showed enhanced survival as compared with
saline-injected mice (Fig. 1
). The
protocol that included a second injection of CRP resulted in greater
protection than the single injection protocol and was used in
subsequent experiments.
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-chain-deficient mice from LPS by CRP
Our previous studies have demonstrated that CRP interacts with
mouse FcR to induce phagocytosis of opsonized particles
(32). In the mouse, phagocytosis of CRP-opsonized
particles is mediated by FcRI and C. Phagocytosis of IgG-coated
particles through FcR can change the cytokine profile of
LPS-challenged mice (28). To determine whether FcRI was
involved in the protective effect of CRP for LPS challenge, mice
deficient in the -chain were studied. These mice do not express
functional FcRI or FcRIII. Unlike the normal mice, no significant
protection from or exacerbation of mortality following LPS challenge
was observed (Fig. 2). These results when
compared with the results in normal mice indicate that a
-chain-dependent receptor is required for the CRP-mediated
protection of mice from LPS. As our previous studies have failed to
detect an interaction of CRP with FcRIII, it is most likely that the
required receptor is FcRI (34, 35).
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RIIb-deficient mice treated
with CRP
As CRP was also shown to bind to FcRIIb in the mouse, the
effect of CRP on the survival of FcRIIb-deficient mice upon LPS
challenge was examined. FcRIIb contains an immunoreceptor
tyrosine-based inhibitory motif in the intracellular region and is a
regulatory receptor in the mouse. FcRIIb-deficient mice were given
two injections of CRP as described above and challenged with LPS. Not
only did CRP not protect FcRIIb-deficient mice from LPS challenge,
but a significant increase in mortality was observed as compared with
saline-treated mice (p = 0.01) (Fig. 3). Thus, FcRIIb is crucially involved
in the protection from LPS mediated by CRP.
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RIIb-deficient mice to LPS
To further examine the mechanism by which FcRIIb-deficient mice
showed increased mortality in response to CRP, the levels of
proinflammatory cytokines in the blood were measured.
FcRIIb-deficient mice or C57BL/6 mice were injected with a sublethal
dose of LPS 2 h after injection with either saline or 200 µg of
CRP. One of the most important mediators of inflammation and tissue
damage produced in response to LPS is TNF. Therefore, TNF levels were
measured at 1, 2, and 4 h after injection of LPS. In C57BL/6 mice,
the levels of TNF induced by LPS challenge were unaffected by the
administration of CRP (Fig. 4). However,
CRP treatment significantly increased the levels of TNF at 1 and 4
h after LPS challenge in FcRIIb-deficient mice
(p < 0.05) (Fig. 4). Therefore, one of the
factors involved in the increased mortality seen in FcRIIb-deficient
mice treated with CRP may be the enhanced levels of TNF present in the
blood.
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(36). The
serum levels of IL-12 in C57BL/6 mice were not changed by LPS or CRP
and LPS treatment. However, FcRIIb-deficient mice treated with CRP
showed dramatically higher levels of IL-12 at 1, 2, and 4 h after
administration of LPS (Fig. 5). These
results suggest that the increased mortality in FcRIIb-deficient
mice may be due to an enhanced production of IL-12 and TNF induced
by CRP.
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RIIb-deficient, and FcR -chain-deficient mice to LPS
One of the primary mediators of IL-12 regulation is the
anti-inflammatory cytokine, IL-10. Recent studies of the
interaction of IgG complexes with FcR suggest that this interaction
enhances the production of IL-10 in response to LPS (27).
Furthermore, these studies showed that the production of IL-10 was
associated with protection of mice from LPS. It has been demonstrated
that IL-10 production by macrophages is associated specifically with
the ligation of -chain-associated FcR. As CRP has recently been
demonstrated to bind FcRI, it was postulated that CRP could protect
mice from lethality due to LPS challenge by ligation and cross-linking
of FcRI. The levels of IL-10 in the serum of the three groups of
mice were compared (Fig. 6). In wild-type
mice, CRP treatment resulted in an increase in IL-10 at 1 and 4 h.
In -chain-deficient mice, the IL-10 response was very low (<500
pg/ml) in the presence or absence of CRP. In the FcRIIb-deficient
mice, an increase in IL-10 was also observed although it proved not to
be protective.
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To directly examine the effect of CRP on LPS-stimulated
macrophages, BMM were obtained from C57BL/6 mice. The cultures were
incubated with LPS in the presence of CRP or saline and supernatants
were collected after 8 h. Consistent with the results of others,
LPS at doses up to 100 ng/ml did not produce a substantial increase in
IL-10 (28). However, in the presence of CRP at 100 µg/ml
there was a marked increase in IL-10 levels in response to LPS at
concentrations of 10 and 100 ng/ml. CRP was not directly able to
stimulate IL-10 production as shown by the absence of any IL-10
production at the lowest dose of LPS. As expected, LPS produced a
substantial increase in the production of IL-12 by BMM. In the presence
of CRP, there was a marked decrease in the production of IL-12 at
concentrations of LPS of 10 and 100 ng/ml and these decreases were
statistically significant (Fig. 7). The
increase in IL-10 was not observed when BMM from FcR
-chain-deficient mice were tested (Fig. 7). BMM from
-chain-deficient mice produced higher levels of IL-10 in response to
LPS alone which may have contributed to their increased resistance to
LPS. Thus, CRP can change the balance of pro- and anti-inflammatory
cytokines by macrophages stimulated with LPS, and this response
requires FcR -chain. This activity would be expected to protect mice
in vivo from the toxic effects of LPS.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. Furthermore, there is a balance in the
interaction of CRP with the activating FcR, FcRI, and the
regulatory FcR, FcRII. The presence of the -chain-dependent
FcR is required for CRP to provide protection from LPS, as FcR
-chain-deficient mice were not protected by CRP. In contrast,
CRP-mediated protection was also abrogated in FcRIIb-deficient mice.
These findings suggest that the effect of CRP on the response to LPS is
complex and depends on the interaction between pro- and
anti-inflammatory responses. The ability of CRP to protect mice from challenge with LPS was first demonstrated in a model in which rabbit CRP was expressed as a transgene responsive to diet manipulation (17). These authors showed that CRP protected from LPS as well as platelet-activating factor and galactosamine and low dose LPS, but not from TNF- induced mortality. These results suggested that the effect of CRP was perhaps upstream of TNF.
The lowest dose of CRP tested that produced protection from LPS in the
present study was 500 µg. As the blood volume of the mouse is
2.5–3 ml, this corresponds to 150–175 µg/ml at the initial
point after injection. These levels are seen in moderately severe
inflammatory reactions in humans. As human CRP is cleared with a
half-life of 4 h in the mouse (37), the levels must be
low during most of the exposure time for LPS. Thus, CRP has a
relatively potent in vivo effect.
It has been demonstrated using IgG complexes and IgG-coated E that
cross-linking of FcR selectively induces the production of IL-10
while down-regulating the production of IL-12 (27, 28).
IL-10 is a potent inhibitor of TNF, IL-1, and IL-12 production and is
protective from endotoxin shock (38). IL-12 is a potent
proinflammatory molecule and overexpression of IL-12 is associated with
LPS-induced mortality (28, 39).
Immune complexes are expected to diminish the toxicity of LPS during Gram-negative infection. The relevance of this mechanism to acute Gram-negative sepsis is unclear, as patients with Gram-negative sepsis do not necessarily have significant levels of immune complexes. However, patients with Gram-negative infection have a very strong acute phase response with the production of very high levels of CRP and other acute phase reactants. Therefore, one of the major functions of the acute phase proteins and especially CRP may be to alter the cytokine profile to favor a moderated response to LPS.
There are several ways that the innate immune system can protect mice
from challenge by Gram-negative organisms and endotoxic shock. Others
have shown an important role for C and natural IgM Abs to LPS in
clearing LPS from circulation (40, 41). Still others have
shown that other acute phase reactants are protective from LPS
including 
1-acid glycoprotein
(42) and TSG-14 (43). The acute phase
reactants are uniquely able to rapidly respond to inflammatory and
toxic challenges by bacterial products. The adaptive immune system is
positioned to provide later more specific responses to these
mediators.
In several respects, the activity of CRP in the regulation of macrophage responses to LPS are similar to those of IgG (27, 28). However, in the case of IgG, receptor ligation was accomplished by providing a ligand. In contrast, no exogenous ligand was required for the modulation of LPS responses by CRP in vitro or in vivo. It is possible that the multimeric nature of CRP allows it to cross-link receptors without a ligand (44) or that an unknown ligand is present. It is also possible that CRP interacts with a variety of ligands in vivo under conditions of acute inflammations. These ligands could include nuclear Ags released from dying or apoptotic cells, phospholipids in damaged membranes, and polycationic proteins released from activated neutrophils (reviewed in Ref. 2). In vivo it is likely that damaged tissue provides ligands for CRP. We have been unable to detect CRP binding to LPS by ELISA or any effect of CRP on binding of LPS to CD14-positive monocytes either in the presence or absence of serum.
The crucial role of FcRI in the regulation of inflammatory responses
has been demonstrated. Macrophages from FcRI-deficient and
FcRIII-deficient mice, but not FcR -chain-deficient mice
up-regulate IL-10 in response to immune complexes (27, 45). Thus, for IgG pathways, involving either FcRI or
FcRIII may mediate the same effect. Binding and functional assays
indicate that CRP interacts with FcRI, but not with FcRIII
(21, 32). The in vivo importance of FcRI has recently
been confirmed (45, 46) despite the presumed constant
occupancy of the receptor by IgG2a in vivo.
The enhanced mortality in mice deficient in FcRIIb was unexpected as
this receptor provides no positive signaling and leads to no known
product. FcRIIb does inhibit the activation of immunoreceptor
tyrosine-based activation motif-containing receptors through the
recruitment of the Src homology 2 domain containing inositol
phosphatase (47). If the protective effect of CRP
is mediated through interaction with FcRI, as suggested by the
failure of CRP to protect mice deficient in the -chain, then the
absence of FcRIIb may allow for a stronger activation of the
activating receptors through either CRP or natural IgG. This is
supported by the prolonged TNF response to LPS and the increased
synthesis of IL-12 induced by CRP in FcRIIb-deficient mice. However,
the identity of the signaling pathway on which FcRIIb is acting
remains uncertain. Experiments designed to examine the mechanisms
involved in this effect are planned.
It has been reported that the induction of IL-10 is specific to
interactions through the FcR, but that the down-regulation of IL-12
synthesis may occur through other receptors, e.g., C receptors
(48). Thus, the current findings are consistent with our
earlier studies on the interaction of CRP with FcR. In humans, CRP
is present at high concentration during Gram-negative sepsis and is
expected to interact strongly with FcRI and FcRII but not
FcRIII.
Previous studies have suggested that CRP plays an anti-inflammatory role in models where polymorphonuclear leukocyte (PMN) influx and damage are predominant (15, 49). These studies suggest that CRP has a direct effect on PMN activation and trafficking. However, it also seems likely that the interaction of CRP with macrophages could regulate PMN activation through the generation of IL-10 and other anti-inflammatory cytokines, e.g., IL-1RA.
It was reported recently that transgenic mice expressing human CRP are
resistant to experimental allergic encephalomyelitis (50).
These investigators reported an increase in IL-10 production in
cultures of encephalitogenic, nylon wool-enriched T cells incubated
with APC and CRP. Although they concluded that CRP acted directly on T
cells to decrease production of macrophage-inflammatory
protein-1, they postulated that IL-10 production could also
contribute to the protection from experimental allergic
encephalomyelitis by CRP. Our results are consistent with these
findings and expand upon them, showing a reciprocal decrease in IL-12
implicating FcR ligation as the mediator of these cytokine
alterations. Our studies have focused on CRP interaction with
macrophages and we have not yet examined whether T cells are involved
in this regulation.
The synthesis of CRP is stimulated primarily by IL-6 and levels of CRP
are strongly correlated with serum levels of IL-6. Although CRP can
activate the complement cascade and enhance phagocytosis, it now
appears likely that a major function of CRP is to broadly down-regulate
the inflammatory response. This inhibition is mediated by ligation of
FcRI, which leads to the production of IL-10 and the down-regulation
of IL-12 responses to LPS. The timing of CRP in the acute phase
response would appear to be ideally suited for such a regulatory role.
Thus, in addition to its role as a scavenger molecule that recognizes
the products of cell damage and necrosis to ensure their clearance, CRP
is positioned to limit the inflammatory damage induced by infection or
trauma.
The results of these experiments suggest that the actions of CRP (and
other members of the innate immune system) are complex. CRP can protect
from infectious organisms at low doses through interaction with the C
system by activating phagocytosis and clearance of Streptococcus
pneumoniae (51). CRP can also potently down-regulate
the response to proinflammatory stimuli like LPS by binding to FcR,
stimulating the production of IL-10 and blocking the production of
IL-12. These experiments are the first to define a requirement for the
FcRs in an in vivo process mediated by CRP.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Terry W. Du Clos, Department of Veterans Affairs Medical Center, Research Service 151, 1501 San Pedro Southeast, Albuquerque, NM 87108. E-mail address: tduclos{at}unm.edu
3 Abbreviations used in this paper: CRP, C-reactive protein; BMM, bone marrow macrophage; PMN, polymorphonuclear leukocyte.
Received for publication August 14, 2002. Accepted for publication October 11, 2002.
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S. Black, A. Wilson, and D. Samols An Intact Phosphocholine Binding Site Is Necessary for Transgenic Rabbit C-Reactive Protein to Protect Mice against Challenge with Platelet-Activating Factor J. Immunol., July 15, 2005; 175(2): 1192 - 1196. [Abstract] [Full Text] [PDF]
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 H. Chi, E. Messas, R. A. Levine, D. T. Graves, and S. Amar Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model: Pharmacotherapeutic Implications Circulation, September 21, 2004; 110(12): 1 |
