Cytokines are small proteins that are produced and released from many cells under physiological and pathological conditions. They bind to specific cell-surface receptors present on target cells, inducing an intracellular signalling cascade that may alter certain cell functions, such as cell-specific functions, proliferation, migration, adhesion and apoptosis. Many cytokines act synergistically either by binding to the same cell-surface receptor, or by overlapping of intracellular signalling molecules. Many cytokines have pleiotropic functions that even allow induction of antagonistic effects by a single cytokine. Cytokines were first described as immunomodulating agents, and to date host defence ranks as their most prominent function. Without cytokines, the fast, efficient and multifaceted immune response challenged every day would not be possible. Many more features have been ascribed to cytokines, giving rise to cytokine subgroups with specific activities. These include interleukins, growth factors, interferons and chemokines. In embryonal development, cytokines induce or suppress regulators that are essential for patterning, development of organs and differentiation of cells. These cytokines may have functions in the adult that are totally different to those in embryogenesis, or they may be closely related. These examples demonstrate that the cytokine network spun between single cells, tissues and organs follows highly complicated rules that are far from understood .
The liver follows these rules by hosting cells that are highly susceptible for the action of cytokines [2,3]. Hepatocytes bear a variety of cytokine receptors. Receptors for interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1β), tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) may gain control over synthesis of plasma proteins that are produced mainly by hepatocytes. Moreover, receptors for growth factors such as insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) may control proliferation of hepatocytes during embryogenesis or loss of hepatocytes after acute liver injury. Cytokine receptors of hepatocytes may also be involved in the development of liver diseases such as hepatocarcinogenesis.
Non-parenchymal cells complete the picture of the liver being a cytokine-administrated organ by their ability to synthesize a variety of cytokines. Kupffer cells (KCs), resident tissue macrophages, are shown to synthesize pro-inflammatory cytokines such as interleukin 1 (IL-1), IL-6 and TNF-α upon activation due to phagocytosis or binding of activation-triggering compounds such as endotoxin . Released cytokines may stimulate hepatocytes and other non-parenchymal cells in a paracrine manner. Activation of KCs may also be induced by cytokines such as interferon gamma (IFN-γ), whose receptors are expressed on KCs. Chemokines are released by KCs and mediate immigration of neutrophils and blood monocytes supported by chemokine release from hepatic stellate cells (HSCs). Sinusoidal endothelial cells are targets for pro-inflammatory cytokines to express cell adhesion molecules and may also produce such cytokines. In liver fibrosis, KCs and HSCs are important sources for transforming growth factor beta (TGF-β), the paracrine or autocrine key mediator of increased deposition of extracellular matrix proteins [5,6].
Cytokines in liver development
Development of the liver during early embryogenesis may share similarities with pathophysiological processes seen in adulthood, such as acute liver injury and liver regeneration. The regulation of this complex cascade of signalling events under the influence of cytokines may lead to conclusions with high clinical impact. We will give a short overview of what is known about the involvement of cytokines in liver development (Table 1).
The liver derives from the endoderm, which in whole needs the activity of the TGF-β signalling molecules Vg1 and VegT for development in Xenopus eggs from which most of the data of early embryogenesis have been collected . In turn, both induce a variety of signalling molecules that are related closely to TGF-β. The liver then develops from a dorsal region of the early endoderm. The homeobox gene Hex is expressed in those cells that differentiate into the embryonal liver, indicating that this gene may have a specific regulatory function for the differentiation of the early liver. Again, TGF-β signalling is involved in the regulation of Hex expression.
Differentiation of the hepatic endoderm then may be dependent on fibroblast growth factor 1 (FGF-1) and fibroblast growth factor 2 (FGF-2) , while proliferation of the hepatoblasts seems to depend strongly on hepatocyte growth factor (HGF) . Further differentiation of hepatocytes, which can be monitored through the expression of a variety of liver-specific marker proteins, is likely to depend on the activity of further cytokines such as oncostatin M (OSM), a member of the IL-6 cytokine family .
These data suggest that the molecular events during liver development are related to liver pathophysiology in the adult. Availability of (hepatic) stem cells and knowledge of the signalling pathways that lead to hepatocyte differentiation may also allow attempts to manage liver diseases. Moreover, the option to redirect single molecular cascades, primarily by cytokines, could be a new approach to manage liver diseases.
Cytokines in liver regeneration
Unlike other organs, the liver has the unique ability to restore the original organ mass (e.g. after partial hepatectomy or acute toxic injury) within 1 week [11,12]. Cytokines are thought to play a key role in the initial phase of hepatocyte proliferation, as well as in termination of the regenerative process. While many cytokines have proved to stimulate hepatocyte DNA synthesis in vitro, their exact role in vivo remains to be elucidated. In fact, the stimulation of hepatocyte DNA synthesis is preceded by the activation of intracellular signalling pathways, such as signal transducer and activator of transcription 3 (STAT3), as well as induction of transcription factors such as nuclear factor-κB and CCAAT/enhancer-binding protein β , which are activated by IL-6 and TNF-α. Serum levels of both increase shortly after partial hepatectomy.
TNF-α resembles a multifunctional cytokine , and has been shown to be essential for normal liver regeneration. TNF-α antibodies inhibit liver regeneration , and TNF-α receptor-1 (TNF-α R1) knock-out mice also show deficient liver regeneration . Furthermore, TNF-α has been shown to augment liver DNA synthesis when administered after partial hepatectomy that depends on NF-κB activation . Blocking of TNF-α signalling in TNF-α R1-deficient mice caused a strong inhibition of NF-κB and STAT3 activation. Furthermore, these mice show only a minor increase in IL-6 serum levels, indicating that IL-6 is induced primarily by TNF-α. Exogenous administration of IL-6 in these animals reversed STAT3 inhibition as well as defect liver regeneration. Moreover, IL-6-deficient mice develop liver failure after partial hepatectomy . Since TNF-α may not have a mitogenic effect on hepatocytes, it has been suggested that TNF-α primes hepatocytes  to respond to growth factors such as HGF , TGF-α, and EGF . HGF represents a pleiotropic cytokine with a strong DNA synthesis stimulatory effect on hepatocytes in vitro . Moreover, it resembles a mediator of the acute phase response, has morphogenic and mitogenic effects on cells , and has been shown to act as an antifibrotic agent in experimental liver fibrosis . Expression of HGF increases 6–8 h after partial hepatectomy.
TGF-α can be produced by hepatocytes themselves , thus inducing an autocrine loop. Interestingly, elevation of TGF-α levels after partial hepatectomy occurs in parallel to DNA synthesis, but TGF-α knock-out animals feature normal development and liver regeneration, indicating that in vivo TGF-α may be replaced by EGF.
The hepatic acute phase response
When tissue injury exceeds a certain extent, alterations of functions of single cell populations and even whole organ systems can be observed that are summarized as the acute phase response (APR; Fig. 1) . Cytokines are key factors in mediation of the APR. They are released from activated cells (mainly mononuclear phagocytes but also fibroblasts and myofibroblasts) in response to tissue injury, and bind to specific cell-surface receptors on target cells. These cytokines of the APR have pleiotropic effects on many cells of the body. One major part of the APR is focused on the liver , due to the fact that this organ is a prominent source as well as a target of cytokines . First, macrophages, which after activation are generally considered to be the main source of inflammatory cytokines, are present within the liver – KCs lining the hepatic sinusoids are the largest population of resident tissue macrophages of the body . Second, hepatocytes are targets of cytokines of the APR. They synthesize the majority of plasma proteins . The rate of synthesis of many of these proteins is altered during acute phase conditions (acute phase proteins, APPs). Plasma levels of positive APPs increase, and those of negative APPs decrease. The reason for the changes in plasma concentrations of APPs is not well understood, but the fact that many proteins that participate in host defence are positive APPs suggests that changes in plasma concentrations are involved in the resolution of the underlying pathological condition .
KCs have been shown to synthesize a vast array of inflammatory mediators, such as oxygen radicals, complement components, proteases and cytokines . In vitro data from endotoxin-treated KC cultures (experimental endotoxaemia represents the best studied model of the APR) indicate clearly that these cells have a high potential to synthesize the key cytokines of the APR [32–34]. In fact, by being highly phagocytic, they clear the portal blood from endotoxins, bacteria and other pathological agents, and prevent their entry into the systemic circulation . Cytokines are released from activated KC directly into the blood, and are likely to induce the APR in any other organ. Moreover, KC-derived cytokines act in a paracrine manner on protein synthesis of hepatocytes.
The cytokines of the APR can be classified according to their functions into two major groups (Table 2). IL-1-type cytokines include IL-1α, IL-1β, TNF-α and TNF-β. They stimulate the synthesis of some of the positive APPs (type-I APPs), such as C-reactive protein, serum amyloid A, and haemopexin, and inhibit negative APPs such as albumin. IL-6-type cytokines (IL-6, interleukin 11 (IL-11), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), OSM) stimulate type-2 APPs, such as fibrinogen, α1-antitrypsin, haptoglobin and ceruloplasmin. APPs differ from species to species , with new APPs emerging regularly [37,38]. Moreover, some cytokines act on synthesis of APPs similar to IL-1 or IL-6 , or they may enhance or even inhibit their effects .
New insights into the role of single cytokines have come from knock-out mice. IL-6-deficient mice show a severely impaired APR upon tissue damage and infection, such as after turpentine injection, whereas endotoxin-induced alterations are affected only moderately . Moreover, IL-6-deficient mice behave like wild-type animals in response to TNF-α . On the other hand, mice lacking the TNF receptor 1 are resistant to D-galactosamine/endotoxin [43–45].
Turpentine injection induces production of IL-1β and TNF-α, resulting in increased production of IL-6 and subsequent alterations of hepatic APP synthesis. In IL-1β-deficient mice, induction of APP synthesis is almost completely inhibited, probably due to the lack of IL-6 production . In fact, similar results were obtained from IL-6-deficient mice . In contrast, endotoxin treatment of knock-out mice did not reduce induction of APP synthesis, indicating a sequestrial induction of cytokines only in turpentine-induced (local) inflammation [47,48]. The importance of local factors in turpentine injection may be concluded from data of IL-1β converting enzyme (ICE)-deficient mice. In these animals, turpentine injection induces hepatic APP production similar to wild-type animals. Proteases released locally may be responsible for the cleavage of pro-IL-1β, resulting in biologically active IL-1β. In endotoxaemia of ICE-deficient mice, serum concentrations of IL-1β may not be increased due to the lack of locally released proteases .
Moreover, type-I IL-1 receptor-deficient mice had a reduced hepatic APR after turpentine injection, but behaved similarly to wild-type animals in endotoxaemia . Similarly, TNF receptor-deficient mice (55 kDa and 75 kDa) exhibited a wild-type APR in response to endotoxin , suggesting a major redundancy of cytokine action in systemic inflammation.
Intracellular signalling induced by IL-1-type cytokines involves the transcription factors NF-κB and activator protein 1; that induced by the IL-6-type cytokines involves the STAT3/5 transcription factors. An overlapping signalling involving both cytokine families is provided by the mitogen activated protein (MAP) kinase pathway activating the transcription factors of the C/EBPβ family . They may stimulate types 1 and 2 APP.
Cytokines in acute liver injury
In the last few years, it has been suggested that in most cases hepatocellular injury is due not to the damaging agent itself but to the inflammatory cells that have been attracted by the stressed hepatocytes. In contrast to sustained hepatocellular damage, acute hepatitis is a temporary event that finishes with normal liver histology and function (restitutio ad integrum). In fact, hepatotoxins (drugs, infectious agents) may induce a stress situation in hepatocytes with subsequent release of chemokines followed by accumulation of inflammatory cells and subsequent hepatocellular damage (Fig. 2) . Hepatotropic infectious agents such as viruses or activated T-cells may act in a similar manner  and induce accumulation of inflammatory cells that kill hepatocytes .
Hepatocellular stress may activate resident liver macrophages. Moreover, KCs can be activated directly, e.g. by binding of endotoxins via the CD14 receptor. Pro-inflammatory cytokines such as IL-1α, IL-1β and TNF-α are released from KCs, which induces cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on sinusoidal endothelial cells involved in the recruitment of inflammatory cells, such as blood monocytes . Moreover, pro-inflammatory cytokines may be released from mesenchymal liver cells . In fact, it is debated whether mononuclear phagocytes of the liver are the main source of pro-inflammatory cytokines. Further induction of chemokines amplifies the inflammatory cascade [58,59]. Deteriorated hepatocytes may then be removed by mononuclear phagocytes. The classical hypothesis that toxic liver injury is permitted by hepatocellular death and subsequent attraction of inflammatory cells, the latter removing dead hepatocytes, has come into debate, since newer data have shown that ICAM-1, which is crucial for immigration of inflammatory cells into the liver tissue, may be expressed from sinusoidal cells before the appearance of necrotic hepatocytes in the rat model of carbon tetrachloride-induced acute liver injury . TNF-α released early after carbon tetrachloride intoxication participates in the down-regulation of platelet endothelial cell adhesion molecule 1, which may represent an important event in the sinusoidal transmigration of inflammatory cells [60,61].
As hepatocellular integrity can be maintained in patients with chronic inflammation due to hepatitis C virus infection where biochemical response is achieved by interferon treatment, this mechanism may also come into play in virally induced chronic liver disease.
TNF-α proved to be the key mediator in many experimental liver injury models [62,63], including endotoxaemia/D-galactosamine and concanavalin A-induced hepatitis. Due to an early rise of TNF-α levels, pro-inflammatory genes, including cytokines, chemokines, nitric oxide synthetase and adhesion molecules, are induced. This pro-inflammatory activity resembles one of the cascades that are initiated by binding of TNF-α to its receptors TNF-RI or TNF-RII. It is mediated by the transcription factor NF-κB. Downstream signalling of TNF-α may also result in activation of caspases, with induction of apoptosis. Since NF-κB may inhibit apoptosis by induction of anti-apoptotic factors, the balance of these cascades seems to determine the cellular fate. In endotoxaemia/D-galactosamine-induced hepatitis, inhibition of cellular transcription by D-galactosamine blocks the expression of the anti-apoptotic factors by NF-κB, thus favouring apoptosis.
A protective role of interleukin 4 (IL-4) and interleukin 13 (IL-13) has been shown in hepatic injury in the ischaemia/reperfusion model that depended on the activation of signal transducer and activator of transcription 6 . On the other hand, concanavalin A-induced liver injury is augmented by interleukin 12 (IL-12). One mechanism could be the induction of IFN-γ . Interleukin 10 (IL-10) again has been shown to be protective in this model . Similarly, IL-6 seems to cut hepatocellular losses in carbon tetrachloride-induced hepatic injury by limiting hepatic apoptosis and accelerating hepatocyte replication .
Cytokines in liver fibrosis
Chronic hepatocellular damage results in development of liver fibrosis and subsequent liver cirrhosis, which represents a critical step in liver disease with high clinical impact (Fig. 3). The last decade has revealed intriguing news about the cellular and molecular aspects of liver fibrosis . HSCs are viewed as the cell population within the liver that is mainly responsible for increased deposition of extracellular matrix proteins. They must be activated to transform from a resting, fat-storing cell type into myofibroblast-like cells, which then synthesize a broad spectrum of extracellular matrix proteins [69,70]. Sustained hepatocellular damage induces activation of KCs as well as immigration of blood monocytes, which develop into inflammatory mononuclear phagocytes. Together with sinusoidal endothelial cells, these cell lineages release cytokines that act in a paracrine manner to induce activation of HSCs. The key factors involved in the activation of HSCs are TGF-β, platelet-derived growth factor (PDGF) and IGF-I [71–73]. They have a high impact on induction of DNA synthesis (IGF-I, PDGF) and on synthesis of extracellular matrix proteins (TGF-β) in HSCs. Furthermore, inflammatory cytokines such as TNF-α are also thought to modulate HSC extracellular matrix protein synthesis . On the other hand, HSCs are able to release cytokines (chemokines such as monocyte chemoattractant protein-1)  that are involved in recruitment of inflammatory cells , including mast cells , which in turn further activate HSCs by releasing cytokines such as TGF-β and PDGF. This interactive cytokine loop could explain the fatal accumulation of extracellular matrix that eventually results in the multifaceted clinical complications of chronic liver disease also by acting as surviving factors for activated HSCs and activated myofibroblasts [74,76]. TGF-β and TNF-α also up-regulate the synthesis of protease inhibitors in activated HSCs, thus reducing matrix degradation . Liver myofibroblasts that differ morphologically and functionally from activated HSCs may represent a second cell population that is involved in altered matrix production and deposition during liver fibrogenesis  (Fig. 3). They may contribute to liver fibrogenesis by driving fibrosis starting from periportal and pericentral areas, and that eventually connects to fibrotic sinusoids generated by activated HSCs. Interruption of the cytokine networking represents a hopeful new attempt to inhibit development of liver fibrosis. Recent years have heralded the development of a new therapeutic option for the treatment of liver disease: antifibrotic therapy. According to current theory, attempts have been made to block HSC activation by soluble TGF-β receptor , or by adenovirus-mediated transfer of dominant negative TGF-β receptor , delivering initial promising results. A complete resolution of experimental cirrhosis in rats has been observed after transduction of HGF, probably mediated, at least in part, by suppression of TGF-β . Application of anti-inflammatory IL-10 to patients with chronic hepatitis C also showed a decrease of hepatic fibrosis without any impact on viral replication . Even in those cases where treatment of the underlying liver disease is not effective, such as in non-responders to interferon treatment of viral hepatitis, an antifibrotic treatment could be performed. However, further studies are needed to prove the clinical benefit of these strategies.
Cytokines in liver cancer and metastasis
The liver represents a critical organ in human cancer. Hepatocellular carcinoma is one of the most frequent cancers worldwide with increasing incidence, and the liver is the target of most other cancers due to metastasis. Hepatocellular carcinoma is related closely to chronic hepatitis and cirrhosis, implying that alterations in growth control mechanisms during regeneration, which in part are mediated by cytokines, may be involved in hepatic carcinogenesis. Therefore, the involvement of cytokines as mitogens for hepatocytes has been studied in detail in this context. HGF is a considerable hepatic mitogen during liver regeneration. Nevertheless, transformation in hepatoma cells of the HGF gene resulted in a strong decrease of proliferation . IGF-II, another strong mitogen for hepatocytes found in the liver during development, was detected in hepatocellular carcinoma and hepatoma cells . It is expressed in precancerous lesions , and is suggested to be related closely to hepatocarcinogenesis . Furthermore, TGF-α is expressed in hepatoma cells . TGF-α-overexpressing mice develop multifocal hepatocellular carcinoma , and TGF-β-overexpressing animals develop hepatomas at a frequency of about 60%.
The observation that carcinoembryonic antigens can induce TNF-α and IL-1 in KCs with subsequent induction of cell adhesion molecules in sinusoidal endothelial cells may be one mechanism by which circulating cancer cells metastasize to the liver . Generally, it is thought that the microenvironment of the liver plays an important role in liver metastasis by supplying factors that are essential for tumour cell survival and growth. On the other hand, tumour cells need the corresponding receptors to be able to respond to these local factors. Tumour cells, even those deriving from one primary tumour, may be very heterogeneous regarding expression of cytokine receptors. Therefore, adhesion, survival and growth of tumour cells reaching the liver resemble a natural selection. However, this selection may be an organ-specific cascade of events depending on the expression profiles of both tumour cells and the liver. It is evident in those cases where metastases occur only in the liver. Although the single steps of the metastasis cascade are well defined, little is known about the actual factors (cytokines, adhesion molecules, proteases, proteinase inhibitors) that determine growth of liver metastases. It is assumed that detailed knowledge of these factors will deliver powerful new approaches in cancer treatment.
Adhesion of circulating tumour cells resembles a critical step in metastasis to the liver. IL-1β and TNF-α have been shown to augment liver metastasis by inducing vascular cell adhesion molecule 1 on sinusoidal endothelial cells. IL-1 has been suggested to mediate increased adherence of tumour cells by induction of IL-18 . However, selective adherence of tumour cells may not explain exclusively the growth of tumour cells in the liver. Dependency on growth factor receptors such as the HGF and EGF receptors has been demonstrated [90,91].
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