Failure to Regulate TNF-Induced NF-κB and Cell Death Responses in A20-Deficient Mice

Abstract

A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD). TNF dramatically increases A20 messenger RNA expression in all tissues. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely. A20-deficient cells fail to terminate TNF-induced NF-kappaB responses. These cells are also more susceptible than control cells to undergo TNF-mediated PCD. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NF-kappaB responses in vivo.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…This result is in keeping with the absence of an overt hyperactivation of the innate and adaptive immune system in A20 HET mice, which contrasts with what observed in A20 KO mice. 13 However, we noted significantly higher intrahepatic TNF (10-20-fold) and IL-6 (10-15-fold) mRNA levels in HET versus WT livers 2 d post PH (Figures 2c and d). This correlated with significantly higher intra-hepatic inflammation, as gauged by nuclear expression of the NF-κB subunit p65 in the liver, mostly in hepatocytes as evidenced by their larger nuclei size (Figure 2e), and also likely in Kupffer cells.…”

“…This suggests that A20 HET does not result in hyperactivation of the innate or adaptive immune system as homozygous KO does. 13,33 However, intrahepatic levels of TNF and IL-6 following PH were excessively higher and prolonged in HET versus WT livers 4d post PH, likely contributing to derailed LR. 17 This indicates that maladaptive inflammatory responses in HET mice only unveil following injury (in this case PH), and remain contained to the site of injury (here the liver) as systemic inflammation did not worsen.…”

“…4,11,12 A20 homozygous KO mice are born cachectic, and die within 3-6 weeks of birth from systemic inflammation, predominantly in the liver. 13 This highlights A20's prominence in the liver's physiologic anti-inflammatory and anti-apoptotic defense mechanisms. Significant upregulation of A20 in humans and mice livers following hepatectomy suggests that A20 is also an active player in the liver's physiologic regenerative response.…”

“…This procedure is impossible in shortlived cachectic A20 KO mice. 13 Results A20 knockdown provokes lethality by increasing liver damage and impairing hepatocyte proliferation following PH. Two-third PH, a non-lethal procedure in wild-type (WT) mice, resulted in a staggering 42% lethality in HET mice within 7 days (d) of surgery ( Figure 1a).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Moreover, TCR activation was linked to PTCL-NOS with the ITK-SYK fusion gene being present in approximately 10% of cases [52,71], or MYC overexpression due to IRF4 activating fusions [72] mimicking survival signals normally emanating from antigen receptor signaling. Furthermore, missense mutations in TNFAIP3 , encoding the negative regulator of NF-κB activation A20 in T-cells after TCR stimulation [73], mutations in WNT/β-Catenin negative regulators APC and CHD8 , and other genes with known suppressive roles in TCR activation were disease associated [74]. GATA3 and TBX21 expression are both important in T-cell development, and mutations in these genes may be associated with the PTCL-NOS subgroups, representing potential diagnostic predictors and possibly also therapeutic targets [59].…”