A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death

Abstract

An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

“…Genome-wide association studies identified TNFAIP3 as a disease susceptibility locus in several inflammatory diseases, including IBD (29). However, most disease-associated SNPs within the TNFAIP3 locus are located in noncoding regions, and their effects on A20 expression and IBD pathogenesis are unknown (29). Furthermore, SNPs that reduce A20 expression are associated with improved response to anti-TNF drugs (8).…”

NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor

“…TNF-a injection into mice provides an experimental model to study acute inflammation in vivo (Van Bogaert et al, 2011), and it has been shown to enhance the expression of proinflammatory genes in the liver (Catrysse et al, 2016). To investigate the in vivo relevance of our findings, we injected wild-type and c-Rel knockout mice with TNF-a and studied its effect on the in vivo DNA binding of c-Rel and RelA by ChIP as well as on the expression of proinflammatory genes in the liver.…”

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

“…Mediators like IL-1 β and TNF- α could activate NF- κ B in hepatic stellate cells (HSCs) and promote survival of HSCs and fibrogenesis. Recently, it was discovered that ubiquitin-editing protein A20, an important regulator of inflammatory signaling to block NF- κ B activation, prevents the development of chronic hepatic inflammation and cancer by protecting hepatocytes from death [38]. JNK is involved in multiple signaling cascades related with hepatocellular injury, as well as regulating hepatic steatosis and inflammatory gene expression.…”