Balance of inflammatory pathways and interplay of immune cells in the liver during homeostasis and injury

Abstract

Multiple potentially harmful stimuli challenge the liver, the chief metabolic and detoxifying organ of the human body. Due to its central an atomical location, continuous blood flow from the gastrointestinal tract through the hepatic sinusoids allows the metabolically active hepatocytes, the non-parenchymal cells and the various immune cell populations residing and patrolling in the liver to interact with antigens and microbiological components coming from the intestine. Cytokines are key mediators within the complex interplay of intrahepatic immune cells and hepatocytes, because they can activate effector functions of immune cells as well as hepatocytic intracellular signaling pathways controlling cellular homeostasis. Kupffer cells and liver-infiltrating monocyte-derived macrophages are primary sources of cytokines such as tumor necrosis factor (TNF). The liver is also enriched in natural killer (NK) and natural killer T (NKT) cells, which fulfill functions in pathogen defense, T cell recruitment and modulation of fibrogenic responses. TNF can activate specific intracellular pathways in hepatocytes that influence cell fate in different manners, e.g. pro-apoptotic signals via the caspase cascade, but also survival pathways, namely the nuclear factor (NF)-kappaB pathway. NF-kappaB regulates important functions in liver physiology and pathology. The exact dissection of the contribution of recruited and resident immune cells, their soluble cytokine and chemokine mediators and the intracellular hepatocytic response in liver homeostasis and injury could potentially identify novel targets for the treatment of acute and chronic liver disease, liver fibrosis or cirrhosis.