Monocyte activation in alcoholic liver disease

McClain, Craig J.; Hill, Daniell B.; Song, Zhenyuan; Deaciuc, Ion; Barve, Shirish

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

Monocyte activation in alcoholic liver disease☆

Craig J. McClain
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
- Veterans Administration, Louisville, KY 40292, USA
- Corresponding author. Department of Internal Medicine, University of Louisville Medical Center, 550 S. Jackson St., ACB 3rd Floor, Louisville, KY 40292, USA. Tel.: +1-502-852-6991; fax: +1-502-852-0846.(C.J. McClain)
Daniell B. Hill
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
Zhenyuan Song
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA
Ion Deaciuc
- Department of Medicine, University of Kentucky Medical Center, Lexington, KY 40536, USA
Shirish Barve
- Department of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA

Received 18 December 2001; received in revised form 25 January 2002; accepted 9 February 2002.

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.

Keywords: Alcoholic liver disease, Cytokines, Oxidative stress, Monocytes