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 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.
Mandrekar
Pranoti
P
Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. pranoti.mandrekar@umassmed.edu
Szabo
Gyongyi
G
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006519:Hepatitis, Alcoholic / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D018121:Receptors, Cytokine; D051193:Toll-Like Receptors; D014157:Transcription Factors; D000431:Ethanol