Endotoxin and Kupffer cell activation in alcoholic liver disease

Alcohol Research & Health, Winter, 2003 by Michael D. Wheeler

One central component in the complex network of processes leading to the development of alcoholic liver disease is the activation of immune cells residing in the liver (i.e., Kupffer cells) by a substance called endotoxin, which is released by bacteria living in the intestine. Alcohol consumption can lead to increased endotoxin levels in the blood and liver. When activated, Kupffer cells produce signaling molecules (i.e., cytokines) that promote inflammatory reactions as well as molecules called reactive oxygen species (ROS), which can damage liver cells. Endotoxin activates Kupffer cells by interacting with a complex of protein molecules that are located on the outside of the Kupffer cell or which extend into the cell. Binding of endotoxin alters the activities of the proteins in this complex so that they trigger a cascade of biochemical signals in the Kupffer cell, resulting in cytokine and ROS production and, ultimately, liver damage. Because alcohol can enhance endotoxin release and, therefore, Kupffer cell activation, novel approaches to inhibit these processes might help prevent or ameliorate alcoholic liver disease. KEY WORDS: alcoholic liver disorder; chronic AODE (alcohol and other drug effects); endotoxins; Kupffer cell; cell growth and differentiation; biological activation; cell signaling; cytokines; intestinal cell; epithelium; membrane permeability; treatment method

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Alcoholic liver disease progresses through several stages of tissue damage and liver dysfunction. One of the early stages, alcohol-induced steatohepatitis, is characterized by the accumulation of fat molecules in the liver tissue, accompanied by the migration into the liver of cells associated with inflammation processes. These inflammation-promoting cells are attracted to the liver largely because of the activities of a type of immune cell called Kupffer cells, which reside there. (1) To investigate and clarify the contribution of Kupffer cells to the development of alcoholinduced liver injury, researchers studied rats in which they could induce liver disease by continuously administering alcohol. If the animals were first treated with a chemical (i.e., gadolinium chloride) that specifically destroyed their Kupffer cells, they did not develop alcohol-induced liver injury (Adachi et al. 1994). This key finding supports the idea that Kupffer cells play an important role in alcohol's detrimental effects on liver function.

Alcohol activates Kupffer cells primarily through the action of a substance called endotoxin, which is released by certain bacteria normally present in the intestine of humans and other animals. This article describes the interaction between endotoxin and Kupffer cells, particularly the mechanisms by which endotoxin activates signaling pathways within the Kupffer cells, and how these mechanisms contribute to liver injury. The article concludes by discussing how these findings could be translated into new approaches to treating alcoholic liver disease.

WHAT ARE KUPFFER CELLS?

Kupffer cells belong to a class of immune cells called macrophages, which are found throughout most tissues. Macrophages take various actions to eliminate foreign materials (e.g., bacteria or bacterial products) from the body. For example, macrophages can ingest and destroy foreign materials or secrete immune molecules as well as molecules that regulate the functions of other cells involved in the immune response. These regulatory molecules are called cytokines.

Kupffer cells are macrophages that reside in the liver. Their main role--removing bacteria and foreign proteins from the blood--is essential to the liver's primary function, which is cleansing the blood of foreign materials and toxic substances. When no foreign materials are present, Kupffer cells are in a resting state. They can be activated by numerous molecules, including bacterial endotoxins (described in the next section). When activated, Kupffer cells secrete a variety of cytokines, including a molecule called tumor necrosis factor alpha (TNF-[alpha]) and several types of interleukins. All of these molecules can act as inflammatory cytokines--that is, they induce an inflammatory response necessary to remove the offending toxic or foreign molecules and initiate the healing process. (For more information on cytokines and their role in alcoholic liver disease, see the article by Neuman in this issue.)

Macrophages, including Kupffer cells, and related cells appear to increase their production of cytokines in patients with alcoholic liver disease. Clinical observations have revealed that the precursor cells of macrophages (i.e., monocytes) from patients with alcohol-induced hepatitis produced greater amounts of cytokines, particularly TNF-[alpha], than did monocytes from control patients (McClain and Cohen 1989). Moreover, patients with alcoholic liver disease had higher levels of TNF-[alpha] in their blood (Bird et al. 1990). These data have been confirmed in animals chronically exposed to alcohol (Honchel et al. 1992). Such observations suggest that TNF-[alpha] is a critical factor in alcoholic liver disease, a hypothesis that has been confirmed in animal models using rodents (Iimuro et al. 1996; Yin et al. 1999).