N-acetyl-leucinyl-leucinyl-norleucinal inhibits lipopolysaccharide-induced NF-kappaB activation and prevents TNF and IL-6 synthesis in vivo.
The effects of N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), a potent inhibitor of proteolysis catalyzed by proteasomes, on the activation of NF-kappaB in vitro and in vivo have been examined. Confirming earlier observations, ALLN inhibits the activation of NF-kappaB in macrophage cultures stimulated with LPS, resulting in the intracellular accumulation of IkappaB and p105. The synthesis of TNF, a reaction dependent upon NF-kappaB 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-kappaB.
Schow
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SR
CV Therapeutics, Inc., Palo Alto, California 94304, USA.
Joly
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D000818:Animals; D002478:Cells, Cultured; D005240:Feasibility Studies; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis*; D007976:Leupeptins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D015850:Interleukin-6; D007976:Leupeptins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C063261:acetylleucyl-leucyl-norleucinal