Signalling pathways in alcohol-induced liver inflammation☆

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