Cytokines--central factors in alcoholic liver disease

Abstract

Many processes related to the consumption or breakdown of alcohol that contribute to alcohol-induced liver disease are mediated by small proteins known as cytokines, which are produced and secreted by liver cells and many other cells throughout the body. Through a variety of actions, cytokines regulate certain biochemical. processes in the cells that produce them as well as in neighboring cells. For example, in case of an infection, they attract white blood cells to the tissues, triggering an inflammatory response. In the liver, persistent cytokine secretion resulting in chronic inflammation leads to conditions such as hepatitis, fibrosis, and cirrhosis. Cytokines also regulate a process known as programmed cell death, or apoptosis, which is in part responsible for alcohol-induced destruction of liver tissue. Two cytokines-tumor necrosis factor alpha and transforming growth factor beta-play prominent roles in apoptosis. Finally, a cytokine network mediates the harmful effects of a bacterial protein called endotoxin on the liver. Because of their diverse functions, cytokines might make attractive targets in the prevention or treatment of alcoholic liver disease, and researchers already have obtained encouraging results when testing such approaches.

Figure 1

Schematic representation of the process of apoptosis.

Figure 2

Pathways through which alcohol (ethanol) can contribute to apoptosis. Alcohol is broken down (i.e., metabolized) in the liver cells by two enzymes, alcohol dehydrogenase (ALD) and, particularly after chronic alcohol consumption, cytochrome P450 2E1 (CYP2E1). Both enzymes convert alcohol to acetaldehyde, a toxic substance. Some of the acetaldehyde interacts with proteins in the cells, forming compounds called adducts that can activate certain immune cells to produce various cytokines, including interleukins (ILs), interferon gamma (IFN–γ), and tumor necrosis factor alpha (TNF–α). In addition to acetaldehyde, alcohol metabolism by CYP2E1 also generates highly reactive molecules known as reactive oxygen species (ROS), which accumulate primarily in cell structures called mitochondria. ROS normally are eliminated from the cells by compounds known as antioxidants, particularly a small molecule called glutathione (GSH). Alcohol, however, depletes the cell’s GSH stores, thereby further exacerbating ROS accumulation in the mitochondria. This process leads to the release of cytochrome c from the mitochondria, which then activates enzymes called caspases and promotes production of IL–8 in the cell. Finally, alcohol leads to increased levels of a bacterial protein called endotoxin in the blood and in the liver, which activates immune cells called Kupffer cells that reside in the liver. These cells then produce TNF–α, which in turn activates another type of liver cell, the stellate cells, to produce transforming growth factor beta (TGF–β) and collagen, a protein involved in scar tissue formation (fibrosis). TNF–α production also leads to increased production of chemokines (e.g., IL–8), which attract inflammatory cells from the bloodstream to the liver, contributing to liver inflammation. Excess TNF–α and chemokine production also causes increased production of adhesion molecules that play an important role in fibrosis. Thus, all of these diverse pathways contribute to inflammatory reactions and fibrosis and culminate in the induction of apoptosis and organ damage.