Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines

Abstract

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases worldwide, causing fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. In the past few decades, significant progress has been made in our understanding of the molecular mechanisms underlying alcoholic liver injury. Activation of innate immunity components such as Kupffer cells, LPS/TLR4, and complements in response to alcohol exposure plays a key role in the development and progression of alcoholic liver disease (ALD). LPS activation of Kupffer cells also produces IL-6 and IL-10 that may play a protective role in ameliorating ALD. IL-6 activates signal transducer and activator of transcription 3 (STAT3) in hepatocytes and sinusoidal endothelial cells, while IL-10 activates STAT3 in Kupffer cells/macrophages, subsequently protecting against ALD. In addition, alcohol consumption also inhibits some components of innate immunity such as natural killer (NK) cells, a type of cells that play key roles in anti-viral, anti-tumor, and anti-fibrotic defenses in the liver. Ethanol inhibition of NK cells likely contributes significantly to the pathogenesis of ALD. Understanding the roles of innate immunity and cytokines in alcoholic liver injury may provide insight into novel therapeutic targets in the treatment of alcoholic liver disease.

Fig. 1. Molecular mechanisms of alcoholic liver disease (ALD): roles of innate immunity and cytokines

Chronic alcohol exposure leads to innate immunity activation such as Kupffer cells and LPS/TLR4. Activated Kupffer cells produce TNF-α and toxins that contribute to ALD. LPS also stimulates Kupffer cells to produce hepatoprotective cytokines (such as IL-6) and anti-inflammatory cytokines (such as IL-10). Both IL-6 and IL-10 play protective roles in ameliorating ALD via activation of STAT3 in different types of liver cells. Alcohol consumption inhibits IL-6 activation of STAT3 in hepatocytes and sinusoidal endothelial cells, and inhibits IL-10 activation of STAT3 in monocytes, contributing to the pathogenesis of ALD. Alcohol consumption also suppresses some other components of innate immunity such as NK cells. NK cells play important roles in anti-viral, anti-tumor, and anti-fibrotic defenses in the liver. Alcohol inhibits NK cell functions via multiple mechanisms as described in the text, contributing to the pathogenesis of ALD.