[Frontiers in Bioscience 7, d1662-1675, July 1, 2002]


Robert G Batey and Jianhua Wang

Division of Medicine, John Hunter Hospital, Newcastle 2310, NSW Australia


1. Abstract
2. Introduction
3. Pathogenesis of alcohol related liver disease and the role of cytokines
3.1. Pathogenesis of alcohol related liver disease
3.2. Role of cytokines
3.2.1. Cytokines and their regulation in alcohol related liver disease
3.2.2. TNF
a mediation in alcohol related liver disease
3.2.3. IL-6-its role in alcohol related liver disease
4. Immune effects of chronic alcohol consumption on lymphocytes in human and animal experimentation
4.1. Immune abnormalities of peripheral T lymphocytes
4.2. Signal transduction abnormalities of peripheral T lymphocytes
4.3. Immune abnormalities of peripheral B lymphocytes
4.4. Immune abnormalities of peripheral NK lymphocytes
4.5. Immune abnormalities of liver-associated T lymphocytes
5. Intrahepatic T lymphocyte involvement in the pathogenesis of alcohol related liver disease
5.1.Phenotypes, natural immunity and origin of intrahepatic lymphocyte in non-diseased liver
5.1.1. Human intrahepatic lymphocyte populations, numbers and proportions
5.1.2. Natural immune functions of intrahepatic T lymphocytes
5.1.3. Origin and development of intrahepatic lymphocytes
5.2. Intrahepatic T lymphocytes mediate liver injury of alcohol related liver disease
6. Perspective
7. References


The development of alcohol-induced liver injury is, in part, a consequence of the immunological/inflammatory response that alcohol stimulates. The abnormalities of immune function in heavy drinkers have been documented well. Cytokines, especially TNF a, produced from macrophages/Kupffer cells, play a role in the induction of liver cell necrosis and apoptosis. TNF alpha can cause liver cell apoptosis through the TNF alpha receptor or Fas/CD95 which is expressed by liver cells. Furthermore, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNF a and other cytokines. There exists an intrinsic lymphocyte population in the normal liver. Intrahepatic T lymphocytes consist of a heterogeneous population of cells that has many and varied functional characteristics in addition to classical T cell activity. The population of intrahepatic T lymphocytes may arise via a thymus-independent pathway. Our recent work has demonstrated the role of liver-associated T lymphocytes in the pathogenesis of alcohol related liver injury initiated by a variety of stimuli such as endotoxin (lipopolysaccharide, LPS) or concanavalin A (Con A). Our studies have, for the first time, suggested that alcohol consumption alone does not lead to the development of marked liver necrosis (at least in the rat), but rather that a second insult is required for this to occur. Liver-associated T lymphocytes in rats spontaneously secrete interleukin-1 alpha, interleukin-6 and TNF a in vitro culture. There is a significant decline in the amounts of interleukin-1 a and TNF a secreted in ethanol-consuming rats compared with non-ethanol consuming rats. The numbers of T cells, NK cells and Kupffer cells in liver perfusates remains stable over a prolonged period of ethanol consumption. However, following Con A injection, there was an inappropriate increase in the amounts of interleukin-6 and TNF a secreted in in vitro culture of liver-associated T lymphocytes and a significant increase in the percentage of CD4+ T cells and CD25+ T cells in liver perfusates compared with non-ethanol consuming rats. It suggested that liver-associated T lymphocytes are involved in the inflammatory process associated with alcohol related liver injury through increased cytokine secretion (TNF a).