N-Acetyl-leucinyl-leucinyl-norleucinal Inhibits Lipopolysaccharide-Induced NF-κB Activation and Prevents TNF and IL-6 Synthesisin Vivo

Abstract

The effects of N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), a potent inhibitor of proteolysis catalyzed by proteasomes, on the activation of NF-κBin vitroandin vivohave been examined. Confirming earlier observations, ALLN inhibits the activation of NF-κB in macrophage cultures stimulated with LPS, resulting in the intracellular accumulation of IκB and p105. The synthesis of TNF, a reaction dependent upon NF-κB activation, is blocked by ALLN. Treatment of mice with LPS results in the induction of TNF and IL-6 within 90 min followed by lethal shock at 24 hr. In mice pretreated with ALLN, serum TNF and IL-6 levels were significantly lower than those in untreated animals. These studies suggest that the proteasome is a novel target for the identification of agents that may be useful in the treatment of those diseases whose etiology is dependent on the activation of NF-κB.