Review articleMonocyte activation in alcoholic liver disease☆
Introduction
The research focus of our laboratory for more than 15 years has been the activation of monocytes, macrophages, and Kupffer cells in alcoholic liver disease (ALD), subsequent production of proinflammatory cytokines such as tumor necrosis factor (TNF), and consequent production of many of the metabolic complications and the liver injury of ALD (McClain et al., 1999). In this review, we will focus on the role of monocyte activation in ALD and thus the role of monocytes in the pathogenesis of systemic and clinical complications of ALD. Three components will be addressed: (1) evidence for monocyte activation in ALD, (2) potential mechanisms for monocyte activation in ALD, and (3) role of secreted monocyte products (e.g., cytokines) in the systemic sequelae of ALD. For this symposium, we have not addressed the role of other cell types, such as neutrophils and lymphocytes, in the pathogenesis of liver injury, nor the role of Kupffer cells in liver injury. These areas have been reviewed extensively in other participants' papers in these proceedings.
Section snippets
Monocyte activation
There are several ways in which monocyte activation can be documented. One of the most widely used markers is the serum or urinary neopterin level (a nonspecific indicator of monocyte activation). Neopterin is a pyrazino-pyrimidine compound that is produced in large amounts by macrophages after stimulation with interferon-gamma (IFN-γ). Neopterin levels are consistently elevated in ALD (Luna-Casado et al., 1997). Increased levels of adhesion cell molecules such as leukocyte function-associated
Endotoxin, lipopolysaccharide-binding protein, CD14, and Toll-like receptors in alcoholic liver disease
Both portal vein and systemic endotoxemia are well documented in ALD, with increased serum endotoxin levels noted even in patients with only fatty liver Bigatello et al. 1987, Bode et al. 1987. Alcohol consumption increases gut permeability in both experimental animals and human beings Bjarnason et al. 1984, Robinson et al. 1981. However, the relative importance of endotoxin in ALD remains controversial. Why alcohol-dependent subjects should retain responsiveness to LPS instead of developing
Monocyte activation/cytokine systemic effects
Increased circulating levels of cytokines have been postulated to cause many of the metabolic and nutritional abnormalities observed in ALD, especially in AH, and in more decompensated liver disease Hill et al. 1997, McClain et al. 1999. Thus, abnormalities, such as fever, anorexia, muscle breakdown and wasting, and altered mineral metabolism (to name only a few), are likely, at least partially, to be mediated by products from activated macrophages (Fig. 4). We will briefly review alterations
Conclusions and future directions
Monocyte activation is well documented in patients with ALD. The mechanisms for this are multiple, as outlined in this review. However, critical questions such as why patients with liver disease (a condition in which monocytes are continually exposed to endotoxin) do not develop endotoxin tolerance remain unanswered. The observed monocyte activation, with its subsequent proinflammatory cytokine production, plays a role not only in the liver injury in ALD but in many systemic complications of
Acknowledgements
This research was supported by the National Institutes of Health grants AA01762, AA10496, AA00190, AA12314, and AA00205, and the Department of Veterans Affairs.
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Editor: T.R. Jerrells