Inflammatory Pathways in Liver Homeostasis and Liver Injury |
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Authors: | Tacke Frank Luedde Tom Trautwein Christian |
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Institution: | Medical Clinic III, RWTH-University Hospital Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. frank.tacke@gmx.net |
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Abstract: | The liver is a unique organ with respect to its anatomical location, allowing continuous blood flow from the gastrointestinal
tract through the sinusoids, and its cellular composition, comprising metabolically active hepatocytes, nonhepatocytic parenchymal
cells, and various immune cell populations. Cytokines are key mediators within the complex interplay of intrahepatic immune
cells and hepatocytes, as 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-alpha (TNF-alpha) and interleukin-6. The liver is also enriched in natural killer
(NK) and NK T cells, which fulfill functions in pathogen defense, T cell recruitment, and modulation of liver injury. TNF-alpha
can activate specific intracellular pathways in hepatocytes that influence cell fate in different manners, e.g., proapoptotic
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. Recent experiments with genetically modified mice demonstrated important
and partly controversial functions of this pathway, e.g., in cytokine-mediated hepatocyte apoptosis or ischemia–reperfusion
injury. 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. |
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Keywords: | Inflammation Apoptosis Monocytes NKT cells NF-kB TNF-alpha IL-6 Dendritic cells DC Innate immunity Liver fibrosis |
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