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Defending the liver from inflammation
Christian Trautwein
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische
Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
* To whom correspondence should be sent: Professor Dr. med. C. Trautwein,
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische
Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover
Tel.: +49-511-532-6620, Fax: +49-511-532-5692
Email: [email protected]
INTRODUCTION:
The liver is involved in different tasks of the body. A very old observation is the
induction of the acute phase response which represents a first line of defense in
order to restrict bacterial growth. Different cytokines have been shown to contribute
to this regulation, however interleukin-6 (IL-6) and tumor necrosis factor (TNF)
have been shown to play a prominent role during this process.
In recent years it became obvious that besides regulating the acute phase
response cytokines like IL-6 and TNF are also involved in regulating different
functions during liver physiology. These include an involvement during liver
regeneration, liver failure, cancer development or glucose metabolism. This article
will cover more specifically the molecular mechanisms of IL-6 and TNF-dependent
signaling during liver regeneration and their role during acute liver failure.
Interleukin-6 dependent signal transduction
Interleukin-6 (IL-6) belongs to a family comprising of IL-6, IL-11, leukaemia
inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotropic factor (CNTF) and
cardiotropin 1 (CT-1). They all need the gp130 molecule for signal transduction
(Taga, et al. 1997, Heinrich et al. 1998). Cytokines of the IL-6 family interact with a
receptor complex on the cell surface. In this complex gp130 is the central molecule
as it is used by several family members for signal transduction. IL-6 first binds the IL-
6 receptor (gp80) and then interacts with gp130. Subsequently dimerisation of two
gp130 molecules activates Janus kinases (Jaks), which phosphorylate specific
tyrosine residues of gp130 and thus activate the SHP2/Erk/Map pathways or the
transcription factors STAT1 and STAT3 (Figure 1) (Taga et al. 1997, Heinrich et al.
1998).
Tumour necrosis factor- (TNF)
TNF signals through two distinct cell surface receptors, TNF-R1 and TNF-R2, of
which TNF-R1 initiates the majority of TNF’s biological activities in hepatocytes.
Binding of TNF to its receptor leads to the release of the inhibitory protein silencer of
death domains (SODD) from TNF-R1’s intracellular domain. This leads to the
recognition of the intracellular TNF-R1 domain by the adapter protein TNF receptor
associated death domain (TRADD), which recruits additional adapter proteins:
receptor-interacting protein (RIP), TNF-R–associated factor 2 (TRAF2), and Fas-
associated death domain (FADD). These proteins then activate distinct signaling
cascades (Figure 2).
FADD recruits procaspase-8 via the so called “death-effector-domain” (DED)
of FADD. Procaspase-8 then becomes activated to caspase-8 via the aggregation of
2 or more procaspase-8 molecules by a self-processing mechanism (Ashkenazi &
Dixit 1998) . Activated caspase-8 has been shown to cleave a cytosolic protein called
p22 Bid to its active form, p15 Bid, which translocates to the mitochondria as an
integral membrane protein (Luo et al. 1998, Li et al. 1998). This effects the
mitochondria in a way that leads to the release of cytochrome c, a 12-kDa protein
which normally functions in the mitochondrial electron transport chain. This process
is accompanied by the so called mitochondrial permeability transition (MPT), an
abrupt increase of permeability of the inner mitochondrial membrane to solute
proteins with a molecular mass of less than 1500 Da (Zoratti et al 1995). After
cytochrome c release, caspases are activated, and the cell undergoes apoptosis.
This occurs through the formation of an “apoptosome”, consisting of cytochrome c,
apoptotic protease activating factor-1 (Apaf-1) and procaspase-9. The apoptosome
then recruits procaspase-3, which is cleaved and activated by the active caspase-9
and released to mediate apoptosis.
RAF2 is upstream of several cascades. It activates cIAP-1 and –2, a mitogen
activated protein kinase kinase kinase (MAPKKK) which ultimately activates c-Jun
NH2-terminal kinase (JNK). Additionally TRAF2 is involved in NF-kB activation. Here
also RIP is required, but it does not need its enzymatic activity (for review see Chen
& Goedell 2002).
Activation of NF-kB by TNF requires a complex network of kinases. First the
IKK complex interacts with TRAF2 and RIP. Upon activation the IKK kinase
phosphorylates I-kB which results in its degradation and as a consequence NF-kB is
released to the nucleus where target gene transcription starts.
The high molecular weight IKK complex that mediates the phosphorylation of
I-B has been purified and characterized. This complex consists of three tightly
associated I-B kinase (IKK) polypeptides: IKK1 (also called IKK) and IKK2 (IKK)
are the catalytic subunits of the kinase complex and have very similar primary
structures with 52% overall similarity (DiDonato et al. 1997; Karin 1997, Regnier et al.
1997). Moreover, it contains a regulatory subunit called NEMO (NF-B Essential
Modulator), IKK or IKKAP-1 (Rothwarf et al. 1998, Yamaoka et al. 1998). In vitro,
IKK1 and IKK2 can form homo- and heterodimers (Zandi et al. 1998). Both IKK1 and
IKK2 are able to phosphorylate I-B in vitro, but IKK2 has a higher kinase activity in
vitro compared with IKK1 (Dehase et al. 1999, Woronicz et al. 1997, Zandi et al.
1997).
The IKK complex phosphorylates I-kBs at the N-terminal domain at two
conserved serines (S32 and S36 in human I-B). After phosphorylation, the I-Bs
undergo a second post-translational modification: polyubiquitination by a cascade of
enzymatic reactions, mediated by the -TrCP-SCF complex (or the E3IkB ubiquitin
ligase complex). This process is followed by the degradation of I-B proteins by the
proteasome, thus releasing NF-B from its inhibitory I-B-binding partner, so it can
translocate to the nucleus and activate transcription of NF-B-dependent target
genes (Karin 1999, Yamamoto & Gaynor 2004). Since the enzymes that catalyze the
ubiquitination of I-B are constitutively active, the only regulated step in NF-B
activation appears to be in most cases the phosphorylation of I-B molecules.
Role of IL-6 during liver regeneration
Shortly after the STAT transcription factors were identified (Zhong et al. 1994),
it became evident that there is transient IL-6-dependent STAT3 activation after partial
hepatectomy, which is restricted to the first hours as in turn its inhibitor SOCS3 is
immediately induced and thus limits its activity (Cressmann et al. 1995, Campbell et
al. 2001, Trautwein et al. 1996). The ultimate proof for the relevance of IL-6 for liver
regeneration came from experiment with IL-6-/- mice. First experiments published by
Taub´s group demonstrated that these animals had a defect in hepatocyte
proliferation after partial hepatectomy. Significantly more of the IL-6 -/- animals died
compared to wt control mice (Cressmann et al. 1996). The relevance of these
findings was further underlined as the defect in liver regeneration found in TNFR-1 -/-
mice could be reverted by IL-6 injection (Yamada et al. 1997). Through these two
findings the hypothesis was raised that IL-6 is an essential factor involved in driving
the resting hepatocyte into the cell cycle.
Further experiments aimed at better defining the pathways activated by IL-6
that are essential for liver regeneration. The most prominent factor activated by IL-6
in hepatocytes is STAT3. Treatment of IL-6 -/- mice after partial hepatectomy with
stem cell factor restored Stat3 activation and DNA-synthesis (Ren et al. 2003). As
STAT3 knockout mice are embryonal lethal (Takeda et al. 1997) conditional knockout
mice with a hepatocyte-specific knockout for STAT3 were used to study the role of IL-
6/gp130-dependent STAT3 activation during liver regeneration. These animals also
showed impairment in liver regeneration resembling the results of IL-6 -/- animals (Li
et al. 2002). Therefore these results suggested that especially the STAT3 pathway
seems required for liver regeneration following partial hepatectomy. However in
these animals there was strong STAT1 activation, which is normally not found after
partial hepatectomy. STAT1 is known to mediate opposite effects to STAT3.
Therefore this experimental setting has major problems to solve the role of STAT3
during liver regeneration.
Blindenbacher et al. (2003) performed a careful study in IL-6 -/- mice to better
define the role of IL-6 during liver regeneration. They tested if IL-6 has a direct impact
on hepatocyte proliferation or body homeostasis. By using intravenous or
subcutaneous IL-6 injection the authors found that the role of IL-6 seems not to be
directly involved in stimulating hepatocyte proliferation, but in maintaining body
homeostasis in order to allow normal liver regeneration. These results were further
confirmed in conditional knockout animals for gp130. These animals showed normal
liver regeneration compared to wt animals (Wüstefeld et al. 2003). However after
LPS-injection – mimicking bacterial infection – more of the gp130 -/- animals died
compared to controls and showed impaired hepatocyte proliferation. Taken together,
the work of these groups indicate that IL-6/gp130 is involved in contributing to liver
regeneration through mechanism that are not directly related to cell cycle control.
At present the pathways which are relevant to mediate this effect are not
completely understood. However in recent years several reports demonstrate that IL-
6 activates anti-apoptotic pathways also in hepatocytes. Earlier experiments by
Kovalovich et al. demonstrated that IL-6 can activate BcL-xL expression and also a
role for activating Akt has been suggested (Kovalich et al. 2001, Streetz et al. 2003).
Therefore these results indicate that IL-6/gp130 might be relevant to directly protect
hepatocytes during cell cycle progression.
Additionally, IL-6 induces pathways involved in mediating immune-dependent
mechanisms. IL-6 via STAT3 is the major cytokine to induce the acute phase
response (APR) in the liver. The APR is also involved in the regulation of other
pathophysiological mechanisms e.g. macrophage activation, interaction with the
complement system (Strey et al. 2003). Besides controlling APR expression, IL-6
contributes to the regulation of the TH1/TH2 response (Betz et al. 1998). Therefore
these IL-6 dependent tasks could also be relevant in contributing to body
homeostasis after partial hepatectomy.
Role of TNF during liver regeneration
NF-B was first identified in the liver as a factor that is rapidly activated within 30
minutes after PH (Cressmann et al. 1994). The importance of NF-B and TNF
signalling was further confirmed by the fact that liver regeneration is defective in
TNF- receptor1 knockout mice that do not show hepatic NF-B activation after PH
(Yamada et al. 1997).
The question remained if NF-B is able to directly promote hepatocyte
proliferation in this model. NF-B has been shown to be able to directly stimulate the
transcription of genes that encode G1-phase cyclins, and a B-site is present within
the cyclin D1 promoter (Guttridge et al. 1999, Hinz et al. 1999). Additionally,
experiments using an adenovirus of non-degradable I-kB superrepressor, which
blocks NF-kB activation, indicated that NF-kB activation after partial hepatectomy is
required for liver regeneration. Animals treated with the virus showed a lack of
hepatocyte proliferation and increased apoptosis (Limuro et al. 1998).
In contrast, Chaisson et al. used transgenic mice that expressed the non-
degradable I-kB superrepressor specifically in hepatocytes, but only 60% of the
hepatocytes expressed the transgene. These mice – in contrast to the adenovirus
experiments - showed normal hepatocyte proliferation after PH (Chaisson et al.
2002). However, both systems, which were used to block NF-kB activation, have
some experimental problems. Therefore at present it is unclear which level of NF-kB
activation is required to allow normal liver regeneration after partial hepatectomy.
TNF also triggers Junkinase (JNK) activity and c-Jun activation during liver
regeneration (Diehl et al. 1994, Westwick et al. 1995). Both factors are essential for
cell cycle progression after partial hepatectomy. Inhibition of JNK activity results in
reduced hepatocyte proliferation and Go/G1 transition of hepatocytes. However no
impact on apoptosis was observed (Schwabe et al. 2003). Conditional knockout mice
for c-Jun have a severe phenotype after partial hepatectomy as half of the mice die,
showed impaired regeneration, increased cell death and lipid accumulation in
hepatocytes (Behrens et al. 2002). Together these results demonstrate that JNK/c-
Jun activation is crucial to stimulate liver regeneration after partial hepatectomy.
Via FADD, TNF can trigger apoptosis via caspase 8 activation. Fas can use
the same pathway. However in contrast to TNF, hepatocytes are more sensitive to
Fas-induced apoptosis as the counterbalancing effect of NF-kB activation is missing
(Galle et al. 1995). During liver regeneration after partial hepatectomy, hepatocytes
are less sensitive to Fas-induced apoptosis. Additionally, Fas-stimulation enhances
hepatocyte proliferation indicating that the FADD/caspase 8 pathway during liver
regeneration induces pro-proliferative effects (Desbarats & Newell 2000).
TNF in hepatocyte injury and acute hepatic failure
Although very different agents can cause hepatocyte injury and fulminant
hepatic failure (FHF), a lot of studies in patients and animal models have strongly
implicated that soluble cell death cytokines such as TNF and Fas ligand (FasL) -
another member of the TNF superfamily - are involved in the induction of apoptosis
and in triggering destruction of the liver, which ultimately leads to hepatic failure.
TNF was originally identified by its capacity to induce hemorrhagic necrosis in
mice tumors (Carswell et al. 1975), but severe side effects led to a failure of its use
as a systemic anticancer chemotherapeutic agent (Kimura et al. 1987, Feinberg et al.
1998). A very prominent effect was the direct cytotoxic role of TNF for human
hepatocytes, resulting in increased levels of serum transaminases and bilirubin.
Since then, many clinical studies have underlined the crucial role of TNF in fulminant
hepatic failure and other liver diseases. TNF participates in many forms of hepatic
pathology, including ischemia/reperfusion injury, alcoholic and viral hepatitis, and
injury through hepatotoxins (Colletti et al. 1990, Felver et al. 1990, Gonzales-Amoro
et al. 1994, Leist et al. 1997). Exogenous TNF induces fulminant liver failure and
hepatocyte apoptosis in combination with other toxins (Leist et al. 1997). TNF serum
levels are clearly elevated in patients with FHF (Muto et al. 1998). In another study, it
was shown that serum TNF levels were significantly higher in patients who died than
in patients who survived (Bird et al. 1990).
We also analysed in more detail the role of TNF in fulminant hepatic failure.
Serum TNF, TNF-R1 and TNF-R2 levels were markedly increased in patients with
fulminant hepatic failure and these changes directly correlated with disease activity.
In explanted livers of patients with FHF, infiltrating mononuclear cells expressed high
amounts of TNF and hepatocytes overexpressed TNF-R1. Moreover, the number of
apoptotic hepatocytes was significantly increased in livers from FHF-patients, and
there was a strong correlation with TNF- expression (Streetz et al. 2000). Thus, it is
very likely that the TNF- system is involved in the pathogenesis of FHF in humans,
and its significance has also been shown in several animal models of hepatic failure,
e.g. in the endotoxin/D-galactosamine (GalN) and the concavalin A (ConA) model
(Pfeffer et al. 1993, Ganter et al. 1995).
First described in 1989 (Trauth et al. 1989), the interaction between Fas
receptor and FasL has become a well characterized extracellular system triggering
apoptosis (Krammer. et al 1999, Galle & Krammer 1998). Hepatocytes constitutively
express Fas (APO-1/CD95). A single-dose of an activating anti-Fas-antibody can
lead to apoptosis and cell death in parenchymal and non-parenchymal liver cells
(Ogasawara et al. 1993, Bait et al. 2000) and there is god evidence that this
mechanism is also important during liver fulminant hepatic failure.
IL-6: a protective cytokine in the context of liver failure?
In terms of apoptosis, a lot of experiments showed a role for gp130 in
promoting antiapoptotic effects in different cell types. Activation of STAT3 in B cells
and human myeloma cells causes activation of antiapoptotic genes such as bcl-2 and
bcl-xl and protects these cells from Fas dependent apoptosis (Catlett-Falcone et al.
1999). Similar results were found in T cells. STAT3 deficient T-cells were severely
impaired in IL-6 induced proliferation which was due to the profound defect in IL-6
mediated prevention of apoptosis. In hepatocytes, IL-6 protects from transforming
growth factor- (TGF-) induced apoptosis by blocking TGF- induced activation of
caspase-3 via rapid tyrosine phosphorylation of phosphatidylinositol 3 kinase (PI 3
kinase) which constitutively activated the protein kinase Akt (Chen et al. 1999).
In humans, there is strong evidence that IL-6 is directly involved in the
pathogenesis of different diseases, including multiple myeloma and congestive heart
disease (Ludwig et al. 1991, Tsutamato et al. 1998). Recently, we analysed the
potential role of IL-6 in the development of acute and chronic liver injury in humans
and examined the pathophysiological basis in animal models. We found a direct
correlation of IL-6 expression in serum and liver tissue with disease progression in
FHF patients. Additionally, we could show abolished acute phase response and an
increased susceptibility to LPS-induced liver injury in mice deficient for functional
gp130 in hepatocytes (Streetz et al. 2003). Therefore, IL-6 withholds a protective
function in hepatic failure.
Role of IL-6 in the Concabavalin A model
Concanavalin A (Con A) is a leptin with high affinity towards the hepatic sinus
(Tiegs et al. 1992). Accumulation of Con A in the hepatic sinus results in the
activation of liver natural killer T (NKT) cells, i.e. NK 1.1 CD4+ CD8- TCR+ and
NK1.1. CD4- CD8- TCR+ , that are essential to trigger the early phase of Con A-
induced liver injury (Takeda et al. 2000, Kaneko et al. 2000). Consecutively CD4-
positive and polymorphonuclear cells are attracted to the hepatic sinus and trigger an
increase of cytokines like TNF, IL2, IFN IL-6, GM-CSF and IL-1 (Trautwein et al.
1998). Con A-induced liver damage resembles liver injury in humans i.e. autoimmune
or viral hepatitis. Therefore this model might be ideal to potentially identify molecular
mechnaims that result in new treatment options als in humans.
TNF and IFN have direct implications for the induction of liver cell injury, as
anti-TNF and anti-IFN antibodies protect from Con A-induced liver injury (Gantner
et al. 1995, Küsters et al. 1996) and IFN and TNF -/- mice are resistant to Con A
induced liver cell damage.
Early results demonstrated that IL-6 might be protective in this model as
treatment of the animals with this cytokine protected from Con A-induced liver injury
(Mizuhara et al. 1994). Our recent experiments further characterised the molecular
mechanisms that are important to confer liver protection. Interestingly, IL-6-
dependent signaling in hepatocytes was essential to protect the animals from liver
injury. Further dissection of the intracellular gp130-dependent pathways in
hepatocytes showed that STAT3 activation directly confers liver protection. Especially
the activation of the acute phase response and the chemokine KC seems to be
involved in order to block Con A-induced liver failure (Klein et al. 2005).
Figure Legends:
Figure 1. Interleukin-6-dependent signaling
On the cell surface Interleukin-6 (IL-6) first interacts with the IL-6 receptor
(IL-6R)/gp80. This complex interacts with gp130 molecules and in turn triggers
intracellular dimerisation. Receptor-bound Janus kinases (JAKs: Jak1/2/Tyk2)
became activated and phosphorylate tyrosines as the intracellular part of gp130. The
phosphorylated tyrosines are essential to activate downstream pathways. While
phosphorylation of the second tyrosine is important to trigger the Ras/Map pathway
via SH2-domain containing protein tyrosine phosphatase 2 (Shp2), the four distal
tyrosines are essential to activate Stat transcription factors.
Figure 2. TNF-dependent signal transduction
Engagement of TNF with its cognate receptor TNF-R1 results in the release of SODD
and formation of a receptor-proximal complex containing the important adapter
proteins TRADD, TRAF2, RIP, and FADD. These adapter proteins in turn recruit
additional key pathway-specific enzymes (for example, caspase-8 and IKK2) to the
TNF-R1 complex, where they become activated and initiate downstream events
leading to apoptosis via caspase 8, NF- B activation involving the IKK-complex, and
Junkinase (JNK) activation.
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