Endotoxin and Kupffer cell activation in alcoholic liver disease

Abstract

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.

Figure 1

Model of the association between endotoxin release, Kupffer cell activation, and liver injury. Following chronic alcohol ingestion, endotoxin released from certain intestinal bacteria moves from the gut into the bloodstream and into the liver. There the endotoxin activates Kupffer cells—a type of immune cell (i.e., macrophages) residing in the liver—by interacting with a molecule called CD14 located on the surface of those cells. This interaction causes the production of the regulatory nuclear factor kappa B (NFκB), which in turn leads to the generation of significant amounts of cytotoxic factors, namely superoxide radicals (O₂^•) and various signaling molecules (i.e., cytokines), most prominently TNF–α. TNF–α has been shown to be an essential factor in the injury to primary liver cells (i.e., hepatocytes) associated with alcoholic liver disease.

Figure 2

How endotoxin activates Kupffer cells in the liver. Endotoxin, also called lipopolysaccharide (LPS), in association with soluble LPS-binding protein (LBP), interacts with a receptor complex consisting of the proteins CD14 and TLR4. This interaction initiates a variety of signaling cascades in the cell. One of these cascades, which involves interleukin–1 receptor-associated kinase (IRAK) and the associated proteins MyD88 and TRAF, acts on a regulatory molecule called nuclear factor kappa B (NFκB), which is inactive in the cell if it is associated with the inhibitory molecule IκBα. In response to the signals initiated by endotoxin binding, IκBα is released from NFκB, leading to activation of NFκB. This activation, in turn, results in a number of different responses, such as the generation of superoxide through the NADPH oxidase complex and the production of cytokines. NOTE: MyD88 = myeloid differentiation factor 88; TRAF = tumor necrosis factor receptor–associated factor.