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and the TNF-p55 receptor
1 Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610; and 2 Amgen, Thousand Oaks, California 91320
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Lipopolysaccharide and
D-galactosamine induced lethality and apoptotic liver
injury is dependent on endogenously produced tumor necrosis factor
(TNF)-
. The present study was undertaken to determine whether
membrane-associated or secreted TNF- signaling through the p55 or
p75 receptor was responsible for survival and hepatic injury after
lipopolysaccharide administration in
D-galactosamine-sensitized mice. Transgenic mice expressing
null forms of TNF-, the p55 and p75 receptor, and mice expressing
only a cell-associated form of TNF- were challenged with 8 mg
D-galactosamine and 100 ng lipopolysaccharide. Mortality
and apoptotic liver injury were only seen in wild-type and p75 knockout
mice. p75 Knockout mice had significantly higher concentrations of
plasma TNF- than any other experimental group (P 
0.05)
and tended to have the highest mortality and liver injury. In contrast,
p55 and TNF- knockout mice and animals expressing only a
cell-associated form of TNF- exhibited no mortality or liver injury.
We conclude that survival and apoptotic liver injury in response to
lipopolysaccharide and D-galactosamine are dependent
exclusively on secreted TNF- signaling through the p55 receptor.
apoptosis, hepatitis, septic shock
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TUMOR NECROSIS FACTOR (TNF)- plays a central role in
both the proinflammatory and apoptotic responses to endotoxemic shock (10, 20). However, TNF- can exist as both a cell-associated (membrane bound) and secreted protein and can transduce its signal by
binding to one of two cellular receptors, type I (p55) or type II (p75)
(11). Although it has been generally presumed that the proinflammatory
properties of TNF- are primarily due to secreted TNF- signaling
through the p55 and not p75 receptor (17, 23, 24), studies by Kollias
and colleagues (1, 12) and Grell et al. (6) have suggested that
cell-associated TNF- signaling through the p75 receptor plays a
contributory role in the development of rheumatoid arthritis and
hepatocyte apoptosis. These investigators have argued that the liver
injury secondary to concanavalin A treatment is not due solely to
secreted TNF- acting through the p55 receptor, but is also the
result of cell-associated TNF- signaling through the p75 receptor
(12). The latter finding is consistent with our own studies that have
demonstrated that blocking the processing of TNF- from its
cell-associated to secreted forms with a matrix metalloproteinase
inhibitor prevents lipopolysaccharide (LPS)-induced lethality but does
not prevent the apoptotic hepatocyte injury (20, 21).
In the present report, we have used both a genetic and pharmacological
approach to resolve the relative contributions of secreted and
cell-associated TNF-, p55- and p75-receptor signaling, to the
lethality and hepatic injury secondary to LPS and
D-galactosamine (D-GalN). Mice expressing null
forms of TNF-, the p55 and p75 receptor, and mice expressing only a
cell-associated form of TNF- were challenged with a lethal dose of
LPS and D-GalN. In addition, wild-type and transgenic mice
were pretreated with a matrix metalloproteinase inhibitor that
effectively prevents the release of the soluble 17-kDa form of TNF-
(20). The results clearly demonstrate that lethality to
LPS is due exclusively to secreted TNF- signaling through the p55
receptor. Similarly, transgenic mice expressing null forms of TNF-
and the p55 receptor, or expressing only a membrane form of TNF- are
completely protected from LPS and D-GalN-induced apoptotic
liver injury. However, treatment of mice with a matrix metalloproteinase inhibitor blocks secreted TNF- release and mortality but does not prevent the liver injury. We conclude that both
the lethality and hepatic injury secondary to D-GalN and LPS are the result of secreted TNF- signaling through the p55 receptor.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Mice and reagents. Mixed-sex, wild-type C57BL/6 mice were
purchased from Charles River Laboratories (Wilmington, MA). To
determine the role of TNF- in survival and hepatic injury, C57BL/6
mice expressing a null form of the TNF-receptor type I (p55) or
TNF-receptor type II (p75;
p55
/ or
p75/, respectively)
were used. p75/ Mice
were obtained from Dr. Kendall Mohler (Immunex, Seattle, WA) (17),
whereas p55/ null
mice were obtained from Amgen (Thousand Oaks, CA.) TNF- (tnf/) null mice were
obtained from Amgen and were on a B6 × 129 background. Mice
expressing only a transmembrane, noncleavable cell-associated form of
TNF- (tnf/ × tnftgA86 ) were obtained from Amgen and were
originally obtained from George Kollias (Hellenic Pasteur Institute,
Athens, Greece) (1). These mice were derived from TNF- null
(tnf/) mice
expressing only the 26-kDa transmembrane form of TNF-. The transgene
(tgA86) contains the gene for murine TNF- lacking the wild-type
cleavage site linked to a modified 3' region derived from the
human 
-globulin gene. Appropriate wild-type B6x129 mice were
employed for these studies and were bred in-house at the University of
Florida specific pathogen-free transgenic mouse facility (Gainesville, FL).
LPS derived from Echerichia coli, serotype 0111:B4, D-GalN, and carboxymethylcellulose (CMC) were all obtained from Sigma Chemicals (St. Louis, MO). GM6001 (Ilomastat7), a broad-acting matrix metalloproteinase inhibitor (8, 21), was provided by Dr. Gregory Schultz (Dept. of Obstetrics and Gynecology, Univ. of Florida College of Medicine).
D-GalN/LPS shock model. To block matrix metalloproteinase activity, C57BL/6, B6x129, and transgenic mice (18-24 g) received intraperitoneal injections of 100 mg/kg of body wt of GM6001 in 2% CMC. Control mice received physiological saline in a 200-µl volume, because previous studies had shown that 2% CMC had no effect in this model (20, 21). Thirty minutes later, mice received intraperitoneal injections of 8 mg of D-GalN and 100 ng of LPS. The dose of D-GalN/LPS was based on ~80% mortality by 48 h in wild-type mice. Appropriate mixed sex, age, and background controls (C57BL/6 and B6x129) were used in all experiments with a minimum of 10 mice per group.
At 90 min, mice were either bled retroorbitally for determination of
plasma TNF- bioactivity or were killed by cervical dislocation for
determination of liver membrane TNF- bioactivity. At 8 h, additional
mice were killed and livers harvested for histological analysis. Plasma
glutamic oxalacetic transaminase (GOT)/aspartate aminotransferase (AST)
concentrations were measured using a commercial diagnostic kit (Sigma
Diagnostic, St. Louis, MO). A third group of mice was treated and
survival evaluated over 48 h.
Histological examination. Livers were fixed in 3% buffered Formalin and embedded in paraffin. Sections (5 µm) were affixed to slides and stained with hematoxylin and eosin for morphological changes. Additional slides were processed for immunostaining of apoptotic nuclei using the Apotag kit (Oncor, Gaithersburg, MD) as described by the manufacturer. Briefly, digoxigenin-conjugated nucleotides were catalytically added to DNA fragments by a terminal deoxynucleotidyltransferase (TdT). The 3' ends of the fragments were then labeled with a fluorescein-conjugated anti-digoxigenin antibody. Nuclei were counterstained with propidium iodide.
Isolation of liver membranes. Freshly obtained sections of
livers were homogenized in a Polytron homogenizer with three volumes of
ice-cold homogenization buffer comprised of RPMI 1640 supplemented with
4% bovine serum albumin, 1 mM dithiothreitol, 0.005 mM
phenylmethylsulfonyl fluoride, 0.02% NaN and 0.25 U/ml DNAse. Three
milliliters of homogenate were layered over 2 ml of 41% sucrose
solution and centrifuged at 95,000 g in a SW50.1
swinging-bucket rotor (Beckman Instruments, Palo Alto, CA). The
interfacial band containing the membrane fraction was collected and
resuspended in 5 ml of homogenization buffer. The membranes were washed
and pelleted twice, placed on ice, and assayed immediately for TNF-
bioactivity. Protein content of the purified liver membrane fractions
was also determined using the Lowry technique.
Plasma TNF- bioactivity. Plasma TNF- bioactivity was
determined using the WEHI cytotoxicity assay (4). WEHI 164 clone 13 cells were maintained in 10% heat-inactivated fetal bovine serum
(Mediatech, Herndon, VA) in RPMI 1640 (Mediatech) media supplemented
with 1% penicillin/streptomycin at 37°C in 5% CO2. Two-hundred microliters of 2.5 × 105 cells/ml were
plated onto a 96-well culture plate (Corning, Corning, NY) and
incubated overnight. Media were then replaced with 80 µl/well of the
above media plus actinomycin D at a final concentration of 1.0 µg/ml.
Diluted plasma samples or human recombinant TNF- (Amgen, Boulder,
CO) were added in a volume of 20 µl, and after overnight incubation,
cell viability was measured using the vital dye
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
bromide (MTT, Sigma). 10 µl of MTT (6 mg/ml) were added, media were
removed 4 h later, and the formazan product was dissolved with 100 µl/well of 2-propanol. The amount of TNF- contained in the plasma
samples was calculated from a standard curve using recombinant TNF-. Samples were assayed in duplicate, and the sensitivity of the assay on
undiluted samples was determined to be 5 pg/ml.
Statistics. Data are presented as the means ± SE. The number for each group is between six and 12. Differences among groups were analyzed by one-way analysis of variance. Post hoc comparisons were performed using Student Newman-Keuls multiple-range test. Survival was evaluated by Fisher's exact test. In all cases, statistical significance was assessed with a two-tailed 95% confidence interval.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Survival. D-GalN/LPS produced a consistent
mortality in wild-type mice (Fig. 1).
Overall mortality in the C57BL/6 and B6x129 mice was 59% within 48 h.
Animals started to expire within 4 h of treatment and in general,
mortality was complete within 24-36 h.
tnf/ And
p55/ null mice were
both resistant to D-GalN/LPS-induced lethality with
mortality rates of 0% and 8%, respectively (both P < 0.05 by Fischer's exact test). In contrast, mice lacking a p75 receptor were not protected against D-GalN/LPS-induced lethality.
Although their survival tended to be worse (83%), the differences did
not reach statistical significance compared with appropriate background controls (C57BL/6).
p75/ mice also tended
to die earlier than wild-type mice, with mortality beginning in the
first 3-6 h. Mice expressing only a membrane-associated form of
TNF- (tnf/ × tnftgA86) were completely protected from the lethal
consequences of D-GalN/LPS administration.
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Pretreatment with the matrix metalloproteinase inhibitor GM6001
completely protected wild-type and
p75/ mice from the
lethality associated with D-GalN/LPS administration. Mortality was 10% in wild-type, 0% in
p55/, and 0% in
p75/ GM6001 null mice
(P < 0.05 vs. wild type and
p75/ null, by
Fischer's exact test).
Plasma and liver TNF- responses. The plasma TNF-
responses confirm that the lethality in this model is due to soluble
TNF- acting through p55-receptor signaling. Wild-type mice produced 90-min plasma TNF- responses that ranged between 3,000 and 10,000 pg/ml (Fig. 2; experiments 1 and
2). p55/ and
p75/ both had
increases in plasma TNF- responses compared with wild-type mice, but
statistical significance was only seen in
p75/ mice (P < 0.05). In fact, plasma TNF- concentrations in the p75/ mice were
statistically higher than concentrations in the
p55/ mice. In
contrast, both tnf/
and tnf/ × tnftgA86 mice had no detectable bioactive plasma
TNF-. Taken together, these data suggest that the mortality
associated with D-GalN/LPS was due exclusively to secreted
TNF- acting through the p55 receptor.
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Pretreatment of the mice with GM6001 blocked the plasma TNF-
response by >95% in wild-type,
p55/, and
p75/ mice (Fig. 2,
experiment 2). Plasma TNF- levels in mice treated with
GM6001 had plasma levels that were essentially not different from
healthy control animals.
Liver membrane TNF- levels paralleled the plasma concentrations seen
in wild-type, p55/,
and p75/ mice (Fig.
3). Membrane TNF- levels were highest in
the p75/ mice
followed by the p55/
and wild-type animals. Membrane TNF- was not detected in the livers
of tnf/ null mice,
whereas high levels were expectedly detected in the livers of
tnf/ × tnftgA86 mice. Actually, levels of membrane TNF-
were highest in the tnf/ × tnftgA86 mice (P < 0.05).
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Liver injury response. D-GalN/LPS treatment
produces a characteristic liver injury associated with both areas of
focal necrosis and apoptosis. As shown in Fig.
4, hematoxylin and eosin staining of
hepatocytes from D-GalN/LPS-treated wild-type mice showed
broad areas of necrosis. In addition to cellular necrosis, hepatocyte changes consistent with apoptosis, including shrinkage of cytoplasm, nuclear condensation, and pyknosis, were also seen. Plasma AST/GOT levels were used to document the magnitude of the hepatocyte injury response, and levels were significantly increased in surviving wild-type mice treated with D-GalN/LPS (Fig.
5). It should be noted that both the
histological changes and AST levels were obtained from mice that
survived the 8 h. In some of the groups (wild-type C57BL/6 and
p75/), there was significant mortality within 8 h,
and thus the actual measurements may be underestimates of the true
degree of liver injury in those groups, because only surviving animals
were evaluated.
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In situ terminal deoxynucleotidyl transferase dUTP nick-end labeling
(TUNEL) assay was used additionally to characterize the apoptotic
response (Fig. 6). Stained apoptotic nuclei
were present throughout the liver of D-GalN/LPS-treated
mice, whereas only occasionally apoptotic nuclei were seen in livers
from control mice.
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The hepatic injury response was essentially eliminated in both
tnf/ and
p55/ null mice. Serum
AST/GOT levels were not different from healthy controls (Fig. 5), and
there were only very modest histological changes consistent with
apoptosis. In contrast, the liver injury in
p75/ mice was
significantly greater than in wild-type controls, as determined by
AST/GOT levels. This was also reflected histologically, with larger
numbers of apoptotic nuclei, as determined by TUNEL staining (Fig. 6).
No liver injury was seen in
tnf/ × tnftgA86 mice (Figs. 6 and 7). GOT/AST levels were
slightly increased over levels seen in
tnf/ mice, although
the differences did not reach statistical significance (Fig.
7). Similarly, histological examination
revealed only very modest areas of necrosis and apoptosis, comparable
to that seen in tnf/
mice (Figs. 4 and 6).
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Although pretreatment of mice with GM6001 eliminated the mortality
associated with D-GalN/LPS, it did not prevent the liver injury in the wild-type mice (data not shown and see Ref. 20). It was
somewhat difficult to gauge the actual degree of injury in the control
animals, because C57BL/6 mice not treated with GM6001 were beginning to
expire within 6 h. However, it was clear that hepatic injury was not
reduced. Similarly, in
p75/ mice treated
with GM6001, there was still significant liver injury (data not shown).
Histologically, there was no apparent reduction in the numbers of
apoptotic nuclei, either determined by light microscopy or by
fluorescent microscopy (in situ TUNEL) in either wild-type or
p75/ mice treated
with GM6001 (data not shown and see Ref. 20).
To rule out the possibility that GM6001 might be generally toxic to
animals in vivo, healthy wild-type mice were administered GM6001. There
was no evidence in the healthy mouse that GM6001 treatment had any
effect on liver injury (AST/GOT) (68 ± 6 vs. 78 ± 6 Sigma-Frankel U/ml in healthy C57BL6 mice with and without GM6001) or
plasma or liver TNF- production (all values less than detection limit).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The current studies further delineate the contribution of
cell-associated and secreted TNF- and their signaling by the two TNF
receptors (p55 and p75) to the lethality and apoptotic hepatic injury
associated with D-GalN/LPS administration. Not only does D-GalN/LPS induce shock and lethality, but it also produces
a fulminant liver injury characterized by widespread apoptotic death of
hepatocytes (2). In this regard, the model differs significantly from
administration of LPS alone, which produces only minimal hepatocyte
apoptosis, but significant necrotic death (2). It has been well
established that TNF- plays a central role in the pathology of
LPS-induced lethality, but less is known regarding the role of
cell-associated and secreted TNF- signaling through its two
receptors in the development of apoptotic hepatic injury. This study
was undertaken to explore whether cell-associated TNF-- and
p75-receptor signaling contributed to these processes.
The two TNF- receptors, p55 and p75, differ significantly in their
intracellular signaling domains (11). The p55 receptor contains death
domains essential for the recruitment of TRADD and activation of
caspases, leading to apoptosis. The p75 receptor contains no such death
domains. In contrast, both the p55 and p75 receptors contain TRAF2
binding regions that lead to involvement of NIK and proinflammatory
signaling pathways. Thus both TNF- receptors should theoretically
contribute to inflammatory processes, whereas p55 signaling should
predominate in terms of inducing apoptosis. However, in vitro and in
vivo studies suggest a more complicated signaling pattern, because both
the p55 and p75 receptors can signal apoptosis in inflammatory cells
(7), but only p55-receptor agonists appear to be inflammatory in vivo
(23, 24).
The present results are unequivocal in demonstrating that the lethality
to D-GalN/LPS is exclusively dependent on secreted TNF-
signaling through the p55 receptor. The observation that p55-receptor
signaling is required for lethality is already well established
(17-19) as is the requirement for TNF- (14). The current
findings can now confirm that secreted TNF-, not cell-associated TNF-, is the primary species responsible for this lethality. Mice
expressing exclusively a cell-associated form of TNF-
(tnf/ × tnftgA86) are completely resistant to the lethality
of D-GalN/LPS. It is unlikely that the single amino acid
substitution present in the expressed TNF- renders it biologically
inactive in this regard, because these mice, but not TNF- null,
spontaneously contract rheumatoid arthritis (1) and develop hepatic
injury secondary to concanavalin A (12). In addition, we can recover
biologically active protein from the liver membranes of these mice that
can kill WEHI 164 clone 13 cells.
Rather, the findings presented here are consistent with a body of
pharmacological data that blocking TNF- processing with matrix
metalloproteinase inhibitors protects against
D-GalN/LPS-induced lethality (5, 15, 20). Treatment of both
wild-type and p75 null mice with GM6001 resulted in a complete absence
of plasma TNF- (Fig. 2) and near-complete survival (Fig. 1).
What remains unresolved is whether the apoptotic hepatic injury to
D-GalN/LPS is also mediated solely by secreted TNF-
signaling through the p55 receptor. There are preliminary data to
suggest that cell-associated and p75-receptor signaling contribute to hepatocyte injury in other models of hepatitis. Kusters et al. (12)
reported that mice expressing only the cell-associated form of TNF-
still develop hepatitis to concanavalin A. Furthermore, the hepatitis
is reduced in p75 null mice and exacerbated in mice overexpressing a
human p75 (12).
The findings presented here demonstrate that the liver injury secondary
to D-GalN/LPS is also due exclusively to TNF- signaling through the p55 receptor. TNF- and p55 null mice are resistant to
the apoptotic hepatic injury effects of D-GalN/LPS. These
findings are, therefore, consistent with the observations of Leist et
al. (13) that TNF--mediated liver injury is at least partially dependent on p55 signaling. Surprisingly, p75 null mice actually had an
exacerbated liver injury response compared with wild-type mice. Not
only were AST levels significantly higher (Fig. 5), but the degree of
apoptosis was greater (Fig. 6). One possible explanation for this
observation is that plasma (Fig. 2) and liver membrane TNF-
concentrations (Fig. 3) were higher in the p75 null mice, suggesting
that either clearance of the TNF- by binding to the p75 receptor is
disrupted, or that TNF- expression itself is disregulated. Peschon
has even postulated that the p75 receptor may serve as a decoy, and
eliminating it genetically may direct more TNF- to the bioactive p55
receptor (17).
We can now confirm that unlike concanavalin A-induced hepatitis,
cell-associated TNF- contributes little to the hepatic injury after
D-GalN/LPS administration. Mice expressing the
cell-associated TNF- had only modest increases in AST concentrations
and no evidence of apoptotic injury by in situ TUNEL analysis. These
data are surprising in light of the observation that treatment with
matrix metalloproteinase inhibitors did not protect mice against the apoptotic liver injury, despite abrogation of the secreted plasma TNF- response and improved survival. We believe the answer lies in
the complex role of matrix metalloproteinases to regulate not only the
processing of cell-associated TNF-, but also the shedding of the p55
TNF receptor (3, 16) and membrane-associated Fas ligand (FasL) (9).
Matrix metalloproteinases can block the activation-induced release of
the p55 receptor, making cells more responsive to the biological
effects of TNF-. Similarly, matrix metalloproteinase inhibitors like
GM6001 block the shedding of FasL (9). We have shown that treatment of
mice with GM6001 actually exacerbates hepatic injury to concanavalin A
(10, 21). This increased hepatic injury response was due
presumably to stabilization of FasL or Fas on the cell membranes,
because pretreatment of the mice with a Fas antagonist protected the
animals from concanavalin A- and GM6001-induced liver injury (10). Thus
treatment of mice with the matrix metalloproteinase inhibitor blocked
TNF- processing and the release of secreted protein but may not have
afforded protection due to stabilization of FasL and other inducers of apoptosis. We have previously shown that LPS and D-GalN
induce FasL expression in the liver (22).
In conclusion, the results suggest that both the lethality and
apoptotic liver injury that accompany D-GalN/LPS
administration result primarily from secreted TNF- signaling through
the p55 receptor. Although cell-associated TNF- can be recovered
from liver membranes after D-GalN/LPS administration, it
does not appear to contribute significantly to either the liver injury
or survival. Similarly, p75-receptor signaling appears to play no
functional signal-transduction role, but may actually serve as a decoy receptor.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of General Medical Sciences Grant GM-40586 and United States Public Health Service.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: L. L. Moldawer, Dept. of Surgery, Univ. of Florida College of Medicine, Gainesville, Fl 32610 (E-mail: moldawer{at}surgery.ufl.edu).
Received 26 July 1999; accepted in final form 25 October 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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