Elsevier

Alcohol

Volume 27, Issue 1, May 2002, Pages 53-61
Alcohol

Review article
Monocyte activation in alcoholic liver disease

https://doi.org/10.1016/S0741-8329(02)00212-4Get rights and content

Abstract

Activated monocytes and macrophages have been postulated to play an important role in the pathogenesis of alcoholic liver disease (ALD). Monocyte activation can be documented by measurement of neopterin, adhesion cell molecules, and certain proinflammatory cytokines and chemokines. We first became interested in the role of monocytes and monocyte-derived cytokines in ALD in relation to altered zinc metabolism that occurs regularly in ALD. Patients with ALD have hypozincemia, which responds poorly to oral zinc supplementation. We have shown that in ALD monocytes make a low-molecular-weight substance that, when injected into rabbits, causes prominent hypozincemia. Subsequently, multiple cytokines [especially tumor necrosis factor (TNF) and interleukin (IL)-8] have been shown to be overproduced by monocytes in ALD. We initially showed that monocytes in ALD spontaneously produce TNF and overproduce TNF in response to a lipopolysaccharide (LPS) stimulus, and this could be attenuated by antioxidants in vitro and in vivo. Alterations in the endotoxin-binding protein LPS-binding protein, in CD14, and in the endotoxin receptor Toll-like receptor 4 all may play roles in enhanced proinflammatory cytokine signaling in ALD. Moreover, several groups have documented increased TNF receptor density in monocytes in ALD. Inadequate negative regulation of TNF occurs at multiple levels in ALD. This includes decreased monocyte production of the important antiinflammatory cytokine IL-10 and blunted response to the antiinflammatory properties of adenosine. Finally, generation of reactive oxygen species (which occurs during alcohol metabolism) and products of lipid peroxidation induce production of cytokines, such as TNF and IL-8. In conclusion, there are multiple overlapping potential mechanisms for enhanced proinflammatory cytokine production by monocytes in ALD. We postulate that activation of monocytes and macrophages with subsequent proinflammatory cytokine production plays an important role in certain metabolic complications of ALD and is a component of the liver injury of ALD.

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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