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Review
. 2009 Jun;50(6):1258-66.
doi: 10.1016/j.jhep.2009.03.007. Epub 2009 Mar 28.

Signalling pathways in alcohol-induced liver inflammation

Pranoti Mandrekar  1 , Gyongyi Szabo
Affiliations
Review

Signalling pathways in alcohol-induced liver inflammation

Pranoti Mandrekar et al. J Hepatol. 2009 Jun.

Abstract

The pathogenesis of alcoholic liver injury involves interactions of several intracellular signalling pathways in different cell types of the liver. Alcohol-induced sensitization of liver macrophages to portal endotoxin/lipopolysaccharide (LPS) is considered a hallmark of alcoholic liver disease (ALD). Intracellular mechanisms associated with LPS-induced signalling play a crucial role in the initiation and progression of alcoholic liver injury, and are being extensively explored. LPS recognition by Toll-like receptor 4 (TLR4) on macrophages and other cell types in the liver, activation of downstream signalling pathways culminating in activation of transcription factors such as NFkappaB, AP-1 leads to increased inflammatory cytokine production in ALD. In addition, LPS-induced MAPK such as ERK and p38 also contribute to liver injury. The importance of alcohol-induced reactive oxygen species and interactions with TLR pathways in macrophages leading to inflammation is becoming increasingly evident. Collectively, these signalling pathways induce pro- and anti-inflammatory cytokines that play an important role in ALD. In this review we describe the key signalling intermediates leading to alcohol-induced inflammation in alcoholic liver disease.

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Figures

Fig 1
Fig 1
Cells involved in alcoholic liver injury. Alcohol-mediated increase in gut-derived endotoxin with oxidative stress mechanisms sensitizes hepatic macrophages to release inflammatory cytokines such as TNFα, IL-1β, IL-1α and IL-6 that affects stellate cells and hepatocyte functions. Endotoxin also affects stellate cell and endothelial cell activation and contributes to liver injury.
Fig 2
Fig 2
TLR4 mediated signalling in alcohol-exposed macrophages. Alcohol alters functions of Toll-like receptors TLR4 in the liver resulting in regulation of MyD88 dependent activation of downstream signalling molecules such as IRAK kinase, IKK and NFκB. MyD88-independent, TRIF-dependent activation of IRF3 is also regulated alcohol exposure. Alcohol also induces NADPH oxidase via reactive oxygen species leading to inflammation.
Fig 3
Fig 3
TLR4 mediated MAPK signalling in alcohol-exposed macrophages. Alcohol alters functions of Toll-like receptors TLR4 in the liver resulting in activation of MAP kinases culminating in alteration of binding to transcription factors such as Egr-1, AP-1 and STAT1. Alcohol also affects cytokine mRNA stability via modulation of MAP kinase activity.
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