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, MedizinischeHochschule Hannover, Carl-Neuberg-Strasse 1, 30625 HannoverTel.: +49-511-532-6620, Fax: +49-511-532-5692Email: Trautwein.Christian@mh-hannover.de
INTRODUCTION:The liver is involved in different tasks of the body. A very old observation is theinduction of the acute phase response which represents a first line of defense inorder to restrict bacterial growth. Different cytokines have been shown to contributeto this regulation, however interleukin-6 (IL-6) and tumor necrosis factor α (TNF)have been shown to play a prominent role during this process. In recent years it became obvious that besides regulating the acute phaseresponse cytokines like IL-6 and TNF are also involved in regulating differentfunctions during liver physiology. These include an involvement during liverregeneration, liver failure, cancer development or glucose metabolism. This articlewill cover more specifically the molecular mechanisms of IL-6 and TNF-dependentsignaling 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, leukaemiainhibitory factor (LIF), oncostatin M (OSM), ciliary neurotropic factor (CNTF) andcardiotropin 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 areceptor complex on the cell surface. In this complex gp130 is the central moleculeas it is used by several family members for signal transduction. IL-6 first binds theIL-6 receptor (gp80) and then interacts with gp130. Subsequently dimerisation of twogp130 molecules activates Janus kinases (Jaks), which phosphorylate specifictyrosine residues of gp130 and thus activate the SHP2/Erk/Map pathways or thetranscription factors STAT1 and STAT3 (Figure 1) (Taga et al. 1997, Heinrich et al.1998).Tumour necrosis factor-α (TNF) TNF signals through two distinct cell surface receptors, TNF-R1 and TNF-R2, ofwhich 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 ofdeath domains (SODD) from TNF-R1’s intracellular domain. This leads to therecognition of the intracellular TNF-R1 domain by the adapter protein TNF receptorassociated 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 signalingcascades (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 of2 or more procaspase-8 molecules by a self-processing mechanism (Ashkenazi &Dixit 1998) . Activated caspase-8 has been shown to cleave a cytosolic protein calledp22 Bid to its active form, p15 Bid, which translocates to the mitochondria as anintegral membrane protein (Luo et al. 1998, Li et al. 1998). This effects themitochondria in a way that leads to the release of cytochrome c, a 12-kDa proteinwhich normally functions in the mitochondrial electron transport chain. This processis accompanied by the so called mitochondrial permeability transition (MPT), anabrupt increase of permeability of the inner mitochondrial membrane to soluteproteins with a molecular mass of less than 1500 Da (Zoratti et al 1995). Aftercytochrome 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 apoptosomethen recruits procaspase-3, which is cleaved and activated by the active caspase-9and released to mediate apoptosis. RAF2 is upstream of several cascades. It activates cIAP-1 and –2, a mitogenactivated protein kinase kinase kinase (MAPKKK) which ultimately activates c-JunNH2-terminal kinase (JNK). Additionally TRAF2 is involved in NF-kB activation. Herealso 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 theIKK complex interacts with TRAF2 and RIP. Upon activation the IKK kinasephosphorylates I-kB which results in its degradation and as a consequence NF-kB isreleased to the nucleus where target gene transcription starts. The high molecular weight IKK complex that mediates the phosphorylation ofI-κB has been purified and characterized. This complex consists of three tightlyassociated I-κB kinase (IKK) polypeptides: IKK1 (also called IKKα) and IKK2 (IKKβ)are the catalytic subunits of the kinase complex and have very similar primarystructures with 52% overall similarity (DiDonato et al. 1997; Karin 1997, Regnier et al.1997). Moreover, it contains a regulatory subunit called NEMO (NF-κB Essential
Modulator), IKKγ 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 andIKK2 are able to phosphorylate I-κB in vitro, but IKK2 has a higher kinase activity invitro 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 twoconserved serines (S32 and S36 in human I-κBα). After phosphorylation, the I-κBsundergo a second post-translational modification: polyubiquitination by a cascade ofenzymatic reactions, mediated by the β-TrCP-SCF complex (or the E3IkB ubiquitinligase complex). This process is followed by the degradation of I-κB proteins by theproteasome, thus releasing NF-κB from its inhibitory I-κB-binding partner, so it cantranslocate to the nucleus and activate transcription of NF-κB-dependent targetgenes (Karin 1999, Yamamoto & Gaynor 2004). Since the enzymes that catalyze theubiquitination of I-κB are constitutively active, the only regulated step in NF-κBactivation appears to be in most cases the phosphorylation of I-κB 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 partialhepatectomy, which is restricted to the first hours as in turn its inhibitor SOCS3 isimmediately induced and thus limits its activity (Cressmann et al. 1995, Campbell etal. 2001, Trautwein et al. 1996). The ultimate proof for the relevance of IL-6 for liverregeneration came from experiment with IL-6-/- mice. First experiments published byTaub´s group demonstrated that these animals had a defect in hepatocyteproliferation after partial hepatectomy. Significantly more of the IL-6 -/- animals diedcompared to wt control mice (Cressmann et al. 1996). The relevance of thesefindings 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 twofindings the hypothesis was raised that IL-6 is an essential factor involved in drivingthe resting hepatocyte into the cell cycle. Further experiments aimed at better defining the pathways activated by IL-6that are essential for liver regeneration. The most prominent factor activated by IL-6in hepatocytes is STAT3. Treatment of IL-6 -/- mice after partial hepatectomy withstem cell factor restored Stat3 activation and DNA-synthesis (Ren et al. 2003). As
STAT3 knockout mice are embryonal lethal (Takeda et al. 1997) conditional knockoutmice with a hepatocyte-specific knockout for STAT3 were used to study the role ofIL-6/gp130-dependent STAT3 activation during liver regeneration. These animalsalso showed impairment in liver regeneration resembling the results of IL-6 -/-animals (Li et al. 2002). Therefore these results suggested that especially the STAT3pathway seems required for liver regeneration following partial hepatectomy.However in these animals there was strong STAT1 activation, which is normally notfound after partial hepatectomy. STAT1 is known to mediate opposite effects toSTAT3. Therefore this experimental setting has major problems to solve the role ofSTAT3 during liver regeneration. Blindenbacher et al. (2003) performed a careful study in IL-6 -/- mice to betterdefine the role of IL-6 during liver regeneration. They tested if IL-6 has a direct impacton hepatocyte proliferation or body homeostasis. By using intravenous orsubcutaneous IL-6 injection the authors found that the role of IL-6 seems not to bedirectly involved in stimulating hepatocyte proliferation, but in maintaining bodyhomeostasis in order to allow normal liver regeneration. These results were furtherconfirmed in conditional knockout animals for gp130. These animals showed normalliver regeneration compared to wt animals (Wüstefeld et al. 2003). However afterLPS-injection – mimicking bacterial infection – more of the gp130 -/- animals diedcompared to controls and showed impaired hepatocyte proliferation. Taken together,the work of these groups indicate that IL-6/gp130 is involved in contributing to liverregeneration through mechanism that are not directly related to cell cycle control. At present the pathways which are relevant to mediate this effect are notcompletely understood. However in recent years several reports demonstrate thatIL-6 activates anti-apoptotic pathways also in hepatocytes. Earlier experiments byKovalovich et al. demonstrated that IL-6 can activate BcL-xL expression and also arole 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 protecthepatocytes during cell cycle progression. Additionally, IL-6 induces pathways involved in mediating immune-dependentmechanisms. IL-6 via STAT3 is the major cytokine to induce the acute phaseresponse (APR) in the liver. The APR is also involved in the regulation of otherpathophysiological mechanisms e.g. macrophage activation, interaction with thecomplement system (Strey et al. 2003). Besides controlling APR expression, IL-6
contributes to the regulation of the TH1/TH2 response (Betz et al. 1998). Thereforethese IL-6 dependent tasks could also be relevant in contributing to bodyhomeostasis after partial hepatectomy.Role of TNF during liver regeneration NF-κB was first identified in the liver as a factor that is rapidly activated within 30minutes after PH (Cressmann et al. 1994). The importance of NF-κB and TNFsignalling was further confirmed by the fact that liver regeneration is defective inTNF- receptor1 knockout mice that do not show hepatic NF-κB activation after PH(Yamada et al. 1997). The question remained if NF-κB is able to directly promote hepatocyteproliferation in this model. NF-κB has been shown to be able to directly stimulate thetranscription of genes that encode G1-phase cyclins, and a κB-site is present withinthe cyclin D1 promoter (Guttridge et al. 1999, Hinz et al. 1999). Additionally,experiments using an adenovirus of non-degradable I-kBα superrepressor, whichblocks NF-kB activation, indicated that NF-kB activation after partial hepatectomy isrequired for liver regeneration. Animals treated with the virus showed a lack ofhepatocyte proliferation and increased apoptosis (Limuro et al. 1998). In contrast, Chaisson et al. used transgenic mice that expressed the non-degradable I-kBα superrepressor specifically in hepatocytes, but only 60% of thehepatocytes expressed the transgene. These mice – in contrast to the adenovirusexperiments - showed normal hepatocyte proliferation after PH (Chaisson et al.2002). However, both systems, which were used to block NF-kB activation, havesome experimental problems. Therefore at present it is unclear which level of NF-kBactivation is required to allow normal liver regeneration after partial hepatectomy. TNF also triggers Junkinase (JNK) activity and c-Jun activation during liverregeneration (Diehl et al. 1994, Westwick et al. 1995). Both factors are essential forcell cycle progression after partial hepatectomy. Inhibition of JNK activity results inreduced hepatocyte proliferation and Go/G1 transition of hepatocytes. However noimpact on apoptosis was observed (Schwabe et al. 2003). Conditional knockout micefor c-Jun have a severe phenotype after partial hepatectomy as half of the mice die,showed impaired regeneration, increased cell death and lipid accumulation inhepatocytes (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 usethe same pathway. However in contrast to TNF, hepatocytes are more sensitive toFas-induced apoptosis as the counterbalancing effect of NF-kB activation is missing(Galle et al. 1995). During liver regeneration after partial hepatectomy, hepatocytesare less sensitive to Fas-induced apoptosis. Additionally, Fas-stimulation enhanceshepatocyte proliferation indicating that the FADD/caspase 8 pathway during liverregeneration induces pro-proliferative effects (Desbarats & Newell 2000).TNF in hepatocyte injury and acute hepatic failure Although very different agents can cause hepatocyte injury and fulminanthepatic failure (FHF), a lot of studies in patients and animal models have stronglyimplicated that soluble cell death cytokines such as TNF and Fas ligand (FasL) -another member of the TNF superfamily - are involved in the induction of apoptosisand in triggering destruction of the liver, which ultimately leads to hepatic failure. TNF was originally identified by its capacity to induce hemorrhagic necrosis inmice tumors (Carswell et al. 1975), but severe side effects led to a failure of its useas 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 humanhepatocytes, resulting in increased levels of serum transaminases and bilirubin.Since then, many clinical studies have underlined the crucial role of TNF in fulminanthepatic failure and other liver diseases. TNF participates in many forms of hepaticpathology, including ischemia/reperfusion injury, alcoholic and viral hepatitis, andinjury through hepatotoxins (Colletti et al. 1990, Felver et al. 1990, Gonzales-Amoroet al. 1994, Leist et al. 1997). Exogenous TNF induces fulminant liver failure andhepatocyte apoptosis in combination with other toxins (Leist et al. 1997). TNF serumlevels are clearly elevated in patients with FHF (Muto et al. 1998). In another study, itwas shown that serum TNF levels were significantly higher in patients who died thanin 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 withfulminant hepatic failure and these changes directly correlated with disease activity.In explanted livers of patients with FHF, infiltrating mononuclear cells expressed highamounts of TNF and hepatocytes overexpressed TNF-R1. Moreover, the number ofapoptotic hepatocytes was significantly increased in livers from FHF-patients, and
there was a strong correlation with TNF-α expression (Streetz et al. 2000). Thus, it isvery likely that the TNF-α 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 Fasreceptor and FasL has become a well characterized extracellular system triggeringapoptosis (Krammer. et al 1999, Galle & Krammer 1998). Hepatocytes constitutivelyexpress Fas (APO-1/CD95). A single-dose of an activating anti-Fas-antibody canlead 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 thismechanism 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 inpromoting antiapoptotic effects in different cell types. Activation of STAT3 in B cellsand human myeloma cells causes activation of antiapoptotic genes such as bcl-2 andbcl-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 severelyimpaired in IL-6 induced proliferation which was due to the profound defect in IL-6mediated prevention of apoptosis. In hepatocytes, IL-6 protects from transforminggrowth factor- (TGF-) β induced apoptosis by blocking TGF-β induced activation ofcaspase-3 via rapid tyrosine phosphorylation of phosphatidylinositol 3 kinase (PI 3kinase) which constitutively activated the protein kinase Akt (Chen et al. 1999). In humans, there is strong evidence that IL-6 is directly involved in thepathogenesis of different diseases, including multiple myeloma and congestive heartdisease (Ludwig et al. 1991, Tsutamato et al. 1998). Recently, we analysed thepotential role of IL-6 in the development of acute and chronic liver injury in humansand examined the pathophysiological basis in animal models. We found a directcorrelation of IL-6 expression in serum and liver tissue with disease progression inFHF patients. Additionally, we could show abolished acute phase response and anincreased susceptibility to LPS-induced liver injury in mice deficient for functionalgp130 in hepatocytes (Streetz et al. 2003). Therefore, IL-6 withholds a protectivefunction 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 theactivation of liver natural killer T (NKT) cells, i.e. NK 1.1 CD4 + CD8- TCRαβ+ andNK1.1. CD4- CD8- TCRαβ+ , 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 anincrease of cytokines like TNF, IL2, IFN γ IL-6, GM-CSF and IL-1 (Trautwein et al.1998). Con A-induced liver damage resembles liver injury in humans i.e. autoimmuneor viral hepatitis. Therefore this model might be ideal to potentially identify molecularmechnaims that result in new treatment options als in humans. TNFα and IFNγ have direct implications for the induction of liver cell injury, asanti-TNFα and anti-IFNγ antibodies protect from Con A-induced liver injury (Gantneret al. 1995, Küsters et al. 1996) and IFN and TNF -/- mice are resistant to Con Ainduced liver cell damage. Early results demonstrated that IL-6 might be protective in this model astreatment of the animals with this cytokine protected from Con A-induced liver injury(Mizuhara et al. 1994). Our recent experiments further characterised the molecularmechanisms that are important to confer liver protection. Interestingly, IL-6-dependent signaling in hepatocytes was essential to protect the animals from liverinjury. Further dissection of the intracellular gp130-dependent pathways inhepatocytes showed that STAT3 activation directly confers liver protection.Especially the activation of the acute phase response and the chemokine KC seemsto be involved in order to block Con A-induced liver failure (Klein et al. 2005).
Figure Legends:Figure 1. Interleukin-6-dependent signalingOn 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 triggersintracellular dimerisation. Receptor-bound Janus kinases (JAKs: Jak1/2/Tyk2)became activated and phosphorylate tyrosines as the intracellular part of gp130. Thephosphorylated tyrosines are essential to activate downstream pathways. Whilephosphorylation of the second tyrosine is important to trigger the Ras/Map pathwayvia SH2-domain containing protein tyrosine phosphatase 2 (Shp2), the four distaltyrosines are essential to activate Stat transcription factors.Figure 2. TNF-dependent signal transductionEngagement of TNF with its cognate receptor TNF-R1 results in the release of SODDand formation of a receptor-proximal complex containing the important adapterproteins TRADD, TRAF2, RIP, and FADD. These adapter proteins in turn recruitadditional key pathway-specific enzymes (for example, caspase-8 and IKK2) to theTNF-R1 complex, where they become activated and initiate downstream eventsleading to apoptosis via caspase 8, NF- B activation involving the IKK-complex, andJunkinase (JNK) activation.
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