Meyer S, Kohler N G, Joly A
CV Therapeutics, Inc., Palo Alto, CA 94304, USA.
FEBS Lett. 1997 Aug 18;413(2):354-8. doi: 10.1016/s0014-5793(97)00930-7.
Cyclosporine A is an immunosuppressive agent that is used clinically in the prevention of transplant rejection and development of graft-versus-host disease. Recently, cyclosporine A has been shown to possess anti-inflammatory properties and is capable of inhibiting lipopolysaccharide-induced NF-kappaB activation. Ubiquitin-mediated proteasomal proteolysis plays a critical role in signal-induced NF-kappaB activation since it regulates both IkappaB degradation and p105 processing, it is also involved in the production of peptides for the assembly of MHC class I molecules. We report here that cylcosporine A acts as an uncompetitive inhibitor of the chymotrypsin-like activity of the 20S proteasome in vitro and that it suppresses lipopolysaccharide-induced IkappaB degradation and p105 processing in vivo demonstrating that inhibition of proteasome proteolysis is the mechanism by which cyclosporine A prevents NF-kappaB activation. A structurally unrelated immunosuppressant, rapamycin, did not inhibit the 20S proteasome in vitro.
环孢素A是一种免疫抑制剂，临床上用于预防移植排斥反应和移植物抗宿主病的发生。最近，环孢素A已被证明具有抗炎特性，能够抑制脂多糖诱导的核因子κB（NF-κB）激活。泛素介导的蛋白酶体蛋白水解在信号诱导的NF-κB激活中起关键作用，因为它调节IκB降解和p105加工，还参与了用于组装MHC I类分子的肽的产生。我们在此报告，环孢素A在体外作为20S蛋白酶体胰凝乳蛋白酶样活性的非竞争性抑制剂，并且它在体内抑制脂多糖诱导的IκB降解和p105加工，表明蛋白酶体蛋白水解的抑制是环孢素A阻止NF-κB激活的机制。一种结构不相关的免疫抑制剂雷帕霉素在体外不抑制20S蛋白酶体。
