Intracellular Survival Pathways in the Liver
Intracellular Survival Pathways in the Liver
Recent studies have drawn attention to cytokines as important modulators of hepatocyte cell death during acute and chronic liver disease. Through interaction with cell surface receptors, they activate specific intracellular pathways that influence cell fate in different manners. For example, tumor necrosis factor not only induces proapoptotic signals via the caspase cascade but also activates intracellular survival pathways, namely the nuclear factor (NF)-κB pathway. In this article, we will focus on the function of the NF-κB pathway in liver physiology and pathology. Especially, recent data based on experiments with genetically modified mice will be discussed, which demonstrated important and controversial functions of this pathway e.g. in cytokine-mediated hepatocyte apoptosis, ischemia-reperfusion injury, liver regeneration and the development of hepatocellular carcinoma. Moreover, the role of the interleukin-6 pathway and its possible protective function in the context of liver failure will be summarized.
Cytokines are small-molecular-weight messengers secreted by one cell to alter its own behavior (autocrine messenger), a closely related cell (paracrine messenger) or cells in different organs (endocrine messenger). Thereby, they enable different organs to react properly to changes in their surrounding and thus to maintain the organism in homeostasis. The liver is an exceptional organ in terms of its metabolic, synthetic and detoxifying function. It has the unique potential to regenerate after tissue loss and for example plays an important role in the regulation process that keeps blood glucose stable. All these and many other functions represent the organ's ability to execute the proper reaction toward the body's demands. Therefore, the liver appears to be a preferred source for and target of cytokine signalling, respectively, and at present one can only imagine the incredible complexity of the network connecting cytokines, receptors and signalling pathways in the liver.
Cytokine action is mediated by the interaction of cellular receptors, that signal internally to the nucleus, and external factors that are able to bind these receptors. These networks have evolved early in evolution; pathways with strong homology to human cytokine networks are already found in Drosophila and mollusks. For example, in Drosophila, nuclear factor (NF)-κB-like transcription factors are activated in order to combat infections, and this function represents one major role of cytokine networks in higher organisms like humans. Maintaining the ordered balance between proliferation and controlled cell death (apoptosis) during embryonic development and organogenesis represents another important function of cytokines under physiologic conditions. As these functions are preserved in the adult organism, a disturbance of the critical balance might have deleterious effects.
Hepatic failure takes place when the amount of functioning hepatocytes decreases until the organ is not capable of fulfilling both its metabolic and synthetic functions anymore. Excessive apoptosis has been implicated in a number of acute and chronic liver diseases, e.g. viral and autoimmune hepatitis, cholestatic disease, alcoholic or drug/toxin-induced liver injury and transplantation-associated liver damage, including ischemia-reperfusion injury and graft rejection. Numerous studies in patient samples, cell culture and animal models point to the fact that e.g. acute and chronic liver failure due to various agents like Hepatitis virus is aggravated or even facilitated by the excess signalling of so-called death receptor ligands. However, there is also a group of cytokine-triggered pathways that mediate a survival signal to the hepatocytes. Under certain conditions, the action of these survival pathways can counteract the death signal mediated by e.g. death receptor ligands. In fact, in many instances hepatic failure might represent the deregulation of hepatic homeostasis as a result of an imbalance between damaging and protective signals that are very tightly regulated under physiologic conditions.
In this article, we will focus on the NF-κB pathway. It represents an intracellular survival pathway that is activated in parallel to the proapoptotic caspase cascade by death receptor ligands. Recent studies in animal models could highlight a fundamental role of the NF-κB pathway in the regulation of processes like cell death and proliferation of liver cells, which, when deregulated, form the basis for the occurence of hepatocellular carcinoma (HCC). Moreover, we will introduce the interleukin (IL)-6 signalling pathway which withholds a protective role in many experimental liver disease models.
Recent studies have drawn attention to cytokines as important modulators of hepatocyte cell death during acute and chronic liver disease. Through interaction with cell surface receptors, they activate specific intracellular pathways that influence cell fate in different manners. For example, tumor necrosis factor not only induces proapoptotic signals via the caspase cascade but also activates intracellular survival pathways, namely the nuclear factor (NF)-κB pathway. In this article, we will focus on the function of the NF-κB pathway in liver physiology and pathology. Especially, recent data based on experiments with genetically modified mice will be discussed, which demonstrated important and controversial functions of this pathway e.g. in cytokine-mediated hepatocyte apoptosis, ischemia-reperfusion injury, liver regeneration and the development of hepatocellular carcinoma. Moreover, the role of the interleukin-6 pathway and its possible protective function in the context of liver failure will be summarized.
Cytokines are small-molecular-weight messengers secreted by one cell to alter its own behavior (autocrine messenger), a closely related cell (paracrine messenger) or cells in different organs (endocrine messenger). Thereby, they enable different organs to react properly to changes in their surrounding and thus to maintain the organism in homeostasis. The liver is an exceptional organ in terms of its metabolic, synthetic and detoxifying function. It has the unique potential to regenerate after tissue loss and for example plays an important role in the regulation process that keeps blood glucose stable. All these and many other functions represent the organ's ability to execute the proper reaction toward the body's demands. Therefore, the liver appears to be a preferred source for and target of cytokine signalling, respectively, and at present one can only imagine the incredible complexity of the network connecting cytokines, receptors and signalling pathways in the liver.
Cytokine action is mediated by the interaction of cellular receptors, that signal internally to the nucleus, and external factors that are able to bind these receptors. These networks have evolved early in evolution; pathways with strong homology to human cytokine networks are already found in Drosophila and mollusks. For example, in Drosophila, nuclear factor (NF)-κB-like transcription factors are activated in order to combat infections, and this function represents one major role of cytokine networks in higher organisms like humans. Maintaining the ordered balance between proliferation and controlled cell death (apoptosis) during embryonic development and organogenesis represents another important function of cytokines under physiologic conditions. As these functions are preserved in the adult organism, a disturbance of the critical balance might have deleterious effects.
Hepatic failure takes place when the amount of functioning hepatocytes decreases until the organ is not capable of fulfilling both its metabolic and synthetic functions anymore. Excessive apoptosis has been implicated in a number of acute and chronic liver diseases, e.g. viral and autoimmune hepatitis, cholestatic disease, alcoholic or drug/toxin-induced liver injury and transplantation-associated liver damage, including ischemia-reperfusion injury and graft rejection. Numerous studies in patient samples, cell culture and animal models point to the fact that e.g. acute and chronic liver failure due to various agents like Hepatitis virus is aggravated or even facilitated by the excess signalling of so-called death receptor ligands. However, there is also a group of cytokine-triggered pathways that mediate a survival signal to the hepatocytes. Under certain conditions, the action of these survival pathways can counteract the death signal mediated by e.g. death receptor ligands. In fact, in many instances hepatic failure might represent the deregulation of hepatic homeostasis as a result of an imbalance between damaging and protective signals that are very tightly regulated under physiologic conditions.
In this article, we will focus on the NF-κB pathway. It represents an intracellular survival pathway that is activated in parallel to the proapoptotic caspase cascade by death receptor ligands. Recent studies in animal models could highlight a fundamental role of the NF-κB pathway in the regulation of processes like cell death and proliferation of liver cells, which, when deregulated, form the basis for the occurence of hepatocellular carcinoma (HCC). Moreover, we will introduce the interleukin (IL)-6 signalling pathway which withholds a protective role in many experimental liver disease models.
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