Elsevier

Journal of Hepatology

Volume 50, Issue 6, June 2009, Pages 1258-1266
Journal of Hepatology

Review
Signalling pathways in alcohol-induced liver inflammation

https://doi.org/10.1016/j.jhep.2009.03.007Get rights and content
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open access

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 NFκB, 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.

Keywords

Macrophages
Kupffer cells
TLRs
MAP kinases
Transcription factors

Abbreviations

ALD
alcoholic liver disease
Egr-1
early growth response factor-1
HSF
heat shock transcription factor
IRF
interferon-responsive factor
NFkB
nuclear factor kappa B
MAPK
mitogen activated protein kinase
MyD88
myeloid differentiation primary response gene (88)
STAT
signal transducers and activators of transcription
SOCS
suppressor of cytokine signalling
TLR
Toll-like receptor

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The underlying research reported in the study was funded by the NIH Institutes of Health, NIH AA017357 and AA015283 conference grant. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.