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

TLDR

A20 is a cytoplasmic zinc‑finger protein that suppresses NF‑κB activity and TNF‑mediated programmed cell death, and its expression is strongly induced by TNF in all tissues. A20‑deficient mice exhibit severe inflammation, cachexia, hypersensitivity to LPS and TNF, and premature death, while their cells fail to terminate TNF‑induced NF‑κB signaling and are more prone to TNF‑mediated cell death, demonstrating that A20 limits inflammation by shutting down TNF‑driven NF‑κB responses in vivo.

Abstract

A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor κB (NF-κB) 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-κB 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-κB responses in vivo.