1 Departments of Medicine and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7080; and 2 Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, 30625 Hannover, Germany
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ABSTRACT |
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Tumor necrosis
factor- (TNF-
) functions as a two-edged sword in the liver.
TNF-
is required for normal hepatocyte proliferation during liver
regeneration. It functions both as a comitogen and to induce the
transcription factor nuclear factor-
B, which has antiapoptotic
effects. On the other hand, TNF-
is the mediator of hepatotoxicity
in many animal models, including those involving the toxins
concanavalin A and lipopolysaccharide. TNF-
has also been implicated
as an important pathogenic mediator in patients with alcoholic liver
disease and viral hepatitis.
tumor necrosis factor receptor; concanavalin A; lipopolysaccharide; liver regeneration; viral hepatitis; alcoholic liver disease; fulminant hepatic failure
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INTRODUCTION |
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TUMOR NECROSIS FACTOR- (TNF-
) is a cytokine
produced mainly by activated macrophages and in smaller amounts by
several other cell types. TNF-
exerts a variety of effects on
different cell types and is implicated as an important mediator in
various physiological and pathophysiological conditions. In addition,
it has become clear that TNF-
is an important mediator of apoptosis
(programmed cell death). To better understand the pleiotropic effects
mediated by TNF-
, much effort has been made to characterize the
intracellular pathways by which it impacts various biological processes
such as cell proliferation, inflammation, and apoptosis.
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TNF LIGAND AND RECEPTOR FAMILIES |
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TNF- belongs to a family of nine ligands (TNF-
, lymphotoxin-
,
TNF-
, Fas ligand, OX40L, CD40L, CD27L, CD30L, 4-1BBL, and lymphotoxin-
) that activate structurally related receptor proteins known as the TNF receptor superfamily. Twelve
transmembrane proteins consisting of two identical subunits have been
identified as members of this family: TNF receptor 1 (TNF-R1, p55),
TNF-R2 (p75), TNF-RP, Fas, OX-40, 4-1BB, CD40, CD30, CD27, pox
virus PV-T2, PV-A53R gene products, and the p75 NGFR. TNF-
interacts
with two receptors, TNF-R1 and TNF-R2. Crystallographic studies of the
55-kDa TNF receptor indicated a dimeric protein structure, with the
subunits oriented head to head. From this observation, the molecular
switch model has been developed to explain the interaction between
TNF-
and its receptors. It is based on the hypothesis that a dimeric receptor protein is contacted by a trimeric ligand complex, leading to
a rearrangement in receptor conformation that permits signal transduction through the plasma membrane.
In addition, the apoptosis-signaling receptors death receptor 3 (DR3),
DR4, and DR5, their ligand TRAIL, and a nonsignaling decoy receptor
TRID/DcR are recently identified members of these superfamilies. TRID lacks an intracellular domain and
inhibits apoptotic signaling (25). This may explain the absence of
widespread TRAIL-mediated apoptosis, despite the expression of both
TRAIL and DR4 in a wide variety of tissues. A somewhat similar
situation may exist for TNF-R1 and TNF-R2, in that soluble forms of the receptor are generated by proteolytic cleavage of the extracellular domain. The physiological role of soluble TNF receptors is not completely understood. However, some reports indicate that the interaction between TNF- and the soluble receptors increases the
half-life of TNF-
in the serum. Additionally, the soluble receptors
block the interaction of TNF-
with the transmembrane receptors and
thus act as antagonists of TNF-
(32).
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INTRACELLULAR PATHWAYS ACTIVATED THROUGH TNF RECEPTORS |
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The intracellular regions of TNF-R1 and TNF-R2 lack catalytic kinase
domains. Instead, receptor-associated proteins function as the
transducers in TNF receptor-dependent signaling. The death domain is a
conserved protein-protein interaction motif of ~80 amino acids that
was first identified in the COOH-terminal regions of TNF-R1 and the Fas
receptor. A number of death domain-containing receptor proteins have
been subsequently identified, including reaper, RIP, DR3, DR4, and DR5.
After ligand binding, the death domain of the Fas-associated death
domain protein (FADD) interacts directly with Fas, while FADD binds
TNF-R1 via the adapter protein TNF-R1-associated death domain protein
(TRADD). FADD also contains a death effector domain, which mediates its
interaction with caspase 8/FLICE/MACH, thus linking both receptors to
the caspase cascade activated during apoptosis. A dominant-negative
mutant of FADD that is unable to bind caspase 8 blocks both TNF--
and Fas-induced apoptosis, indicating the critical role of this
interaction for apoptosis signaling from either receptor protein (see
Fig. 1) (4).
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In addition to interacting with FADD, both TNF receptors bind TNF
receptor-associated factors 1 and 2 (TRAF1 and TRAF2), which activate
downstream signaling proteins, including the mitogen-activated protein
kinase family member c-Jun
NH2-terminal kinase (JNK; also known as stress-activated protein kinase) and the transcription factor
nuclear factor-B (NF-
B). TRAF2 homodimers or TRAF1/TRAF2 heterodimers directly bind to a 78-amino acid region at the
COOH-terminal domain of TNF-R2. In contrast, the
NH2-terminal region of TRADD binds
TRAF2, mediating the interaction between TRAF2 and TNF-R1 (10). The
NH2-terminal ring finger domain of
TRAF2 mediates the downstream signals that result in NF-
B
activation. In particular, overexpression of a truncated form of TRAF2
lacking the NH2-terminal ring
finger domain (TRAF2
) acts as a dominant-negative TRAF2 molecule,
blocking NF-
B activation from either TNF receptor (10). However,
recent studies (35) with TRAF2 (
/
) mice show that activation of NF-
B by TNF-
is only mildly impaired in these animals, indicating that NF-
B activation occurs via both
TRAF2-dependent and -independent pathways, perhaps involving other TRAF
family members or RIP. TRAF-interacting protein inhibits the activation of NF-
B by associating with the TNF-R2 complex through its
interaction with TRAF2.
NF-B is normally retained in the cytoplasm through interaction with
its inhibitor I
B and is activated by a recently elucidated kinase
cascade (13). The serine/threonine kinase NF-
B-inducing kinase
directly binds to TRAF2 and in turn activates I
B kinase-
(IKK-
). IKK-
phosphorylates I
B
at serines 32 and 36, resulting in ubiquitination and rapid degradation of I
B by the
proteosome. The loss of I
B binding unmasks nuclear
localization signals on NF-
B, resulting in NF-
B translocation to
the nucleus and transcriptional activation of its target genes. NF-
B
activation results in cellular protection from apoptosis (33), since
blocking NF-
B activation by chemical inhibitors or a dominant
negative form of I
B significantly sensitized cells to
TNF-
-induced apoptosis. NF-
B (p65) (
/
) mice display
massive hepatic apoptosis during development, resulting in
embryological lethality; cell lines derived from these mice exhibit
dramatically decreased viability after TNF-
treatment (5, 6).
TRAF2 also mediates the activation of the JNK pathway, as shown by JNK
inhibition by TRAF2 and in TRAF2 (
/
) mice (19, 24).
TNF-
-mediated induction of JNK involves activation of the small
GTPase Rac1 and the signaling kinases MEKK and MKK4/JNKK/SEK-1. JNK
phosphorylates the activation domains of the transcription factors
c-Jun, ATF-2, and Elk-1. c-Jun and ATF-2 heterodimers induce
transcription of the c-jun gene,
whereas Elk-1 transactivates c-fos.
c-Jun and c-Fos are both members of the activator protein-1 (AP-1)
family of bZIP transcription factors. The role of JNK
activation in apoptosis signaling is controversial. It has been
reported that JNK activity is required for the induction of Fas- and
ceramide-mediated apoptosis in fibroblasts and leukemia cells, as well
as in growth factor-deprived sympathetic neurons. However, other
results demonstrate that JNK activity is not required for
TNF-
-mediated apoptosis in 293, HeLa, and MCF7 cells or Fas-mediated
apoptosis in Jurkat cells (18, 19). Interestingly, lymphocytes derived
from TRAF2 (
/
) mice were sensitized to TNF-
-mediated
apoptosis despite intact activation of NF-
B, suggesting that JNK
activity may play a protective role in this context (35).
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ROLE OF TNF-![]() |
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TNF- plays a key role in the proliferative response of the
regenerating liver. After partial hepatectomy, the remaining
hepatocytes promptly leave G0 and
enter the proliferative stages of the cell cycle. Proliferation
continues until the liver is restored. The interaction between mitogens
and cytokines in this in vivo model of cellular proliferation is under
intense investigation. The hepatic levels of TNF-
are rapidly
increased after partial hepatectomy. It has been found that biliary
epithelial cells and venous endothelial cells (20), not Kupffer cells,
the resident macrophages in the liver, are the source of TNF-
, based
on in situ PCR and the failure of
GdCl3, a Kupffer cell toxin, to
block TNF-
induction and hepatocyte proliferation after partial
hepatectomy. The first evidence for a critical role for TNF-
in
liver regeneration was a demonstration that hepatocyte DNA synthesis is
inhibited after partial hepatectomy in rats pretreated with a
neutralizing TNF-
antibody (1). In these same animals, the induction
of JNK and AP-1 was inhibited, suggesting that TNF-
, JNK, and AP-1
may contribute to hepatic proliferation (6). In primary cultures of
adult rat hepatocytes, incubation with TNF-
promotes the
proliferative actions of hepatic mitogens, supporting the in vivo
evidence that TNF-
potentiates hepatocyte proliferation (6).
The requirement for TNF- as well as the cytokine interleukin-6
(IL-6) in normal hepatic regeneration after partial hepatectomy was
further established by the use of IL-6 and TNF-R1 null mice. Partial
hepatectomy in the IL-6 (
/
) mice resulted in liver
necrosis and failure, with G1 cell
cycle phase abnormalities, including decreased activation of AP-1 and
the absence of activation of Stat3, a transcription factor induced by
IL-6. Partial hepatectomy in TNF-R1 (
/
) mice resulted in
decreased DNA synthesis, delayed restoration of liver mass, and
increased mortality, with an absence of Stat3 and NF-
B activation
(34). In both knockout mice, normal hepatic regeneration was restored
by the administration of exogenous IL-6. These experiments suggest that
TNF-
binds to the TNF-R1 of Kupffer cells or other nonparenchymal
cells, inducing secretion of IL-6. The IL-6 then binds to its receptor
on hepatocytes, leading to the activation of Stat3 (see Fig.
2).
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To assess the role of NF-B induction in liver regeneration after
partial hepatectomy, NF-
B was specifically and selectively blocked
by adenoviral-mediated delivery of an I
B superrepressor that is
resistant to phosphorylation and degradation and thus inhibits NF-
B
activation. Blocking NF-
B increased apoptosis and decreased the
mitotic index after partial hepatectomy, resulting in liver failure
(12). Thus the induction of NF-
B by TNF-
during liver
regeneration appears to be required both to prevent apoptosis and to
allow normal cell cycle progression (Fig. 2).
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ROLE OF TNF-![]() |
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The role of TNF- in liver injury has been studied in several animal
models. By using neutralizing anti-TNF-
antibodies or knockout mice
for TNF-
, TNF-R1, or TNF-R2, it has become evident that TNF-
triggers apoptosis and/or necrosis of hepatocytes in vivo. In
different animal models of liver injury, TNF-
plays a central or an
additive role in the pathogenesis of acute liver injury. Here, we
review the
endotoxin/D-galactosamine
(GalN), TNF-
/GalN, and concanavalin A (ConA) models. Additionally,
TNF-
has an important, but probably not a central, role for liver
injury in alcohol-mediated liver toxicity. In this model, anti-TNF-
antibodies clearly reduce, but do not prevent, liver cell damage (11).
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ENDOTOXIN/GALN MODEL |
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In the endotoxin/GalN model, the bacterial cell wall component
lipopolysaccharide (LPS) is used to initiate the inflammatory response.
Because rodents are less sensitive to LPS exposure than humans, LPS is
combined with the amino sugar GalN to sensitize the animals. GalN is
metabolized in the liver and results in selective depletion of uridine
nucleotides, which specifically inhibits the transcription of
hepatocytes. The essential role of TNF- in the LPS/GalN model has
been shown by comparison of wild-type C3H mice and the
endotoxin-resistant strain C3H/FeJ. An increase in TNF-
levels in
the wild-type C3H mice precedes liver failure, whereas in the resistant
C3H/FeJ strain, the increase in TNF-
levels and the induction of
liver injury are abolished. More specifically, TNF-R1 is required for
the induction of liver damage (26).
During LPS/GalN-induced liver injury, TNF- induces the transcription
of several proinflammatory genes, including chemokines, nitric oxide
synthase, and adhesion molecules, such as intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and
P-selectin. These changes are essential to trigger the extravasation of
neutrophils into the liver parenchyma, which produces cytotoxic liver
cell damage. In this scenario, a stepwise cascade has been described
that consists of three events: 1)
sequestration of neutrophils in the liver vasculature,
2) transendothelial migration, and
3) adherence-dependent cytotoxicity
against hepatocytes. The initial sequestration of neutrophils in the
liver sinusoids seems to be a predominantly passive trapping process
induced by a variety of proinflammatory mediators. However, the
transendothelial migration process is controlled by adhesion molecules
that are expressed on hepatocytes and nonparenchymal cells. The initial
step in transmigration is mediated by VCAM-1, which is expressed on
sinusoidal, endothelial, and Kupffer cells, but not hepatocytes. ICAM-1
seems to be involved at a later step, when it becomes expressed on
hepatocytes. The
-integrins, such as very late activating antigen-4,
are the adhesion molecules on neutrophils that interact with VCAM-1 and
ICAM-1 during transmigration. During the third step,
hepatocyte apoptosis occurs initially, followed by hepatocyte necrosis.
Interestingly, hepatocyte apoptosis is required for transmigration of
neutrophils and subsequent necrosis (14). Thus early apoptosis of
hepatocytes in the LPS/GalN model amplifies the extent of necrotic
liver injury.
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GALN/TNF-![]() |
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The administration of GalN and TNF- triggers apoptosis of
hepatocytes in vivo and in vitro. TNF-R1 knockout mice are resistant to
TNF-
/GalN treatment, demonstrating the essential role of TNF-R1 in
this apoptosis model (17). This suggests that the transcriptional block
induced by GalN directly inhibits synthesis of antiapoptotic proteins
induced by the TRAF2 pathway. In these mice, pretreatment with either
IL-1 or nitric oxide prevents TNF-
/GalN-mediated apoptosis in a
transcription-dependent manner (3). IL-1 via TRAF6 may thus activate
protective genes, parallel to TNF-
via TRAF2/NF-
B. Interestingly,
TNF-R2 knockout mice are more susceptible than wild-type mice to
TNF-
/GalN treatment. Because transcriptional events cannot explain
this observation, other mechanisms have to be invoked (G. Tiegs,
personal communication). One explanation might be that in
the absence of TNF-R2 more TNF-
is available to bind TNF-R1 and
induce apoptosis. An alternative explanation could be the activation of
additional protective pathways that do not require de novo gene
transcription.
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CONA MODEL |
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ConA is a lectin with high affinity for the hepatic sinus (29). Accumulation of ConA in the hepatic sinus results in an increased influx of circulating lymphocytes into the hepatic sinus and subsequent local proliferation via blastoid formation. The assembly of immune-activated cells in the liver results in an increase of several cytokines that have an essential effect on the degree of liver damage in the ConA model (7, 22, 29). Selective immunosuppression by cyclosporin A or FK506 completely prevents liver injury after ConA injection, demonstrating the important role of T cell activation in this model (22).
Interestingly, the activated lymphocytes start to infiltrate the liver
tissue 8 h after ConA injection, after liver damage has already begun.
In contrast, maximal levels of most cytokines were reached before
infiltration of lymphocytes occurred, showing that the early increase
in cytokine levels is pivotal in triggering liver cell damage (22, 31).
TNF- and IFN-
have been shown to directly contribute to liver
cell damage, since anti-TNF-
and anti-IFN-
antibodies protect
against liver cell damage in this model (7). Additionally, it has been
demonstrated that IFN-
and TNF-
(
/
) mice are
protected from ConA-induced liver cell damage, further supporting the
role of these two cytokines for pathogenesis in the ConA model (15,
28). IL-6 and IL-10 inhibit liver cell damage by reducing the serum
levels of IFN-
and TNF-
, demonstrating the protective effect of
certain cytokines in the ConA model (22).
Until now, a stepwise process of liver damage similar to the
endotoxin/LPS model had not been defined for the ConA model. Adhesion
molecules such as ICAM-1 or VCAM-1 seem to play a minor role, since
mice pretreated with antibodies against either adhesion molecule as
well as ICAM-1 knockout mice still undergo liver cell injury
(Plümpe and Trautwein, unpublished results; Tiegs, unpublished results). However, ICAM-1 expression is clearly upregulated on hepatocytes, which correlates with the strong and immediate activation of NF-B after ConA injection (Ref. 30; J. Plümpe, B. Fregien, and C. Trautwein, unpublished results). It seems possible
that other NF-
B-dependent target genes might trigger mechanisms that contribute to liver injury in this model.
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TNF-![]() |
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TNF- was originally identified by its capacity to
induce hemorrhagic tumors in mice. Attempts to use TNF-
for systemic
anti-cancer chemotherapy have failed due to the appearance of severe
side effects before therapeutic doses could be reached. One of the side
effects of TNF-
treatment was an elevation in serum levels of
transaminases and bilirubin levels, indicating a direct cytotoxic role
of TNF-
in human hepatocytes. Subsequent studies have shown TNF-
may be involved in viral hepatitis, alcoholic liver disease, and
fulminant hepatic failure. TNF-
serum levels are clearly elevated in
patients with fulminant hepatitis (23). In addition, it was found that
serum TNF-
levels were significantly higher in patients who died
than in patients who survived (2). Studies on the expression of TNF-R1
and TNF-R2 during fulminant hepatic failure are still lacking.
A role for TNF- in the pathogenesis of chronic hepatitis B and C
viral infection has been suggested. Both viruses induce TNF-
expression in human liver and human hepatoma cell lines (8). Patients
with chronic hepatitis B have elevated plasma TNF-
levels, and their
peripheral blood mononuclear cells show enhanced TNF-
production in
vitro. In addition, in chronic hepatitis B-infected patients undergoing
interferon-
treatment, a massive increase in spontaneous TNF-
production by blood mononuclear cells was observed at the time of
successful antigen seroconversion (5), suggesting that the increased
TNF-
levels may be involved in hepatitis B virus
clearance. Furthermore, the serum levels of soluble
TNF-R1 and TNF-R2 are significantly elevated in chronic hepatitis B
infection. The serum levels of soluble TNF-R2 correlate closely with
the extent of inflammation and hepatocyte death in the liver. During
interferon therapy, the response and the increase in transaminases are
associated with an increase in soluble TNF-R2 serum levels. For
hepatitis C patients, interferon treatment clears the virus and reduces
TNF-
levels to normal in responsive patients (16). Interestingly,
pretreatment levels of TNF-
were higher in unresponsive compared
with responsive patients (16). Hepatitis C proteins interact with the
TNF receptor, although whether this interaction promotes or prevents
apoptosis is not clear (27).
TNF- serum levels are increased in patients with alcoholic
hepatitis, and the levels correlate inversely with patient survival. TNF-
concentrations were significantly higher in patients who did
not survive an episode of acute alcoholic hepatitis (2). Monocytes
isolated from patients with alcoholic hepatitis spontaneously produced
higher amounts of TNF-
compared with healthy controls. Monocytes
derived from patients with alcoholic hepatitis also produced
significantly more TNF-
in response to LPS than normal monocytes.
Several hypotheses have been developed to explain increased TNF-
levels in patients with chronic ethanol exposure. Chronic ethanol
feeding increases the permeability of the gut to bacterial products
such as LPS, potentially inducing TNF-
production in macrophages
(21). In addition, recent studies investigated the promoter
polymorphism in patients with alcoholic steatohepatitis. These
experiments indicated that patients with alcoholic steatohepatitis had
a mutation in the TNF-
promoter that increases its activity (9).
Thus genetic factors may be involved in the increased TNF-
production in patients with alcoholic hepatitis.
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FOOTNOTES |
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* First in a series of invited articles on Mechanisms of Hepatic Toxicity.
Address for reprint requests: C. Trautwein, Dept. of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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