The role of tumour necrosis factor superfamily receptors and the innate immune system in liver inflammation and epithelial to mesenchymal transition

由于其生理功能，肝脏暴露于各种各样的病原体和毒性损害。因此，它能够通过建立强有力的免疫反应来保护自己免受来自血液的感染。最早被触发的反应被称为“先天免疫反应”，这在进化方面是非常古老的。我们相信这种反应将是决定肝损伤结局的关键。这种反应可能有效地清除了传染性有机体，但在这个过程中可能会对肝脏造成“附带”损害，为了抵消这一点，肝脏可以再生，从而恢复正常的组织结构和功能。如果不小心控制免疫反应和修复反应之间的平衡，结果是持续的、不可逆转的组织损伤、疤痕和最终的癌变。在这个过程中最常见的肝细胞类型是肝细胞和胆管细胞，它们通过分泌促进免疫系统持续激活的因子来造成持续的损伤，从而导致更多的损伤，最终导致肝细胞的癌变。我们提出，在肝细胞表面发现的肿瘤坏死因子受体蛋白家族在决定损伤是否导致损伤因子的清除、再生、修复和完全恢复或持续损伤、瘢痕形成和癌变方面至关重要。这些受体在局部环境中被特定因子（配体）激活，这种激活的结果对广泛的细胞功能非常重要，包括决定细胞是死亡还是增殖。如果一个细胞继续处于增殖状态，控制就会失去，它就会变成癌细胞。因此，这些受体如何、何时、何地被激活，将决定一方面是分解/再生，另一方面是持续损伤和癌变之间的平衡。我们已经开发出了从肝移植过程中移除的肝组织中培养人类细胞的技术，这使我们能够建立系统，利用人类肝细胞来研究这些过程，而不是依赖于动物模型，因为动物模型并不总是准确地代表人类身上发生的事情。我们现在将使用组织培养的人类细胞来研究肿瘤坏死因子受体（TNFr）如何决定肝损伤和修复之间的平衡以及它们在肝脏癌变中的参与。我们计划开展具体的实验，以确定a)控制肝脏中是否存在TNF受体的因素b)这些受体如何控制肝细胞的命运c)“先天”免疫系统如何激活这些过程。d)这种反应是否会导致肝细胞癌变这些研究将告诉我们大量关于肝脏如何对损伤作出反应以及先天免疫系统在这一过程中的作用。这一结果不仅将提供关于正常肝脏功能和对损伤反应的新信息，还可能为开发治疗方法提供新方法，在这种治疗方法中，肝脏对损伤的反应可以被操纵，有利于再生和修复，而不会有癌变的风险。

As a consequence of its physiological functions the liver is exposed to a wide variety of pathogens and toxic insults. Consequently it is capable of protecting itself against infections entering from the blood by mounting a vigorous immune response. The earliest response triggered is called the 'innate immune response' and this is very old in evolutionary terms. We believe that this response will be critical in determining the outcome of liver damage. Such responses may be effective at removing the infectious organism but in the process may cause 'collateral' damage to the liver and to counteract this the liver can regenerate and thereby restore normal tissue architecture and function. If the balance between the immune response and the repair response is not carefully controlled the result is persistent, irreversible tissue damage, scarring and eventually cancerous change. The liver cell types most commonly targetted in these process, hepatocytes and cholangiocytes contribute to persistent damage by secreting factors that promote continuing activation of the immune system which leads to more damage and eventually to the development of a cancerous transformation of the liver cells. We propose that a family of proteins called tumour necrosis factor receptors found on the surface of liver cells are critical in determining whether injury results in removal of the injurious factor, regeneration, repair and full recovery or continuing damage, scarring and cancerous change. These receptors are activated by specific factors (ligands) in the local environment and the outcone of such activation is important for a wide range of cell functions including determining whether a cell dies or proliferates. If a cell continues in the proliferative state control is lost and it can become a cancerous cell. Thus how, when and where these receptors are activated will determine the balance between resolution/regeneration on one hand and persistent damage and cancerous change on the other. We have developed techniques to grow human cells out of liver tissue that is removed during liver transplantation allowing us to set up systems to study these processes using human liver cells rather than relying on animal models which do not always accurately represent what takes place in humans. We shall now use the human cells in tissue culture to investigate how the tumour necrosis factor receptors (TNFr) determine the balance between liver damage and repair and their involvement in cancerous change in the liver. We plan to carry out specific experiments to determine a) the factors that control whether TNF receptors are present in the liver b) how these receptors control the fate of liver cells c) how the 'innate' immune system can activate these processes. d) whether this response can lead to cancerous change in liver cells These studies will tell us a great deal about how the liver responds to injury and the role of the innate immune system in this process. The results will not only provide new information on how the normal liver functions and responds to damage but may also suggest new approaches to developing therapies in which the liver response to injury can be manipulated in favour of regeneration and repair without risking cancerous change.