title: Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation.
abstract: 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.
authors.affiliation: CV Therapeutics, Inc., Palo Alto, CA 94304, USA.
authors.forename: S
authors.initials: S
authors.lastname: Meyer
authors.forename: N G
authors.initials: NG
authors.lastname: Kohler
authors.forename: A
authors.initials: A
authors.lastname: Joly
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D016572:Cyclosporine / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011090:Polyenes / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020123:Sirolimus; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011090:Polyenes; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C063261:acetylleucyl-leucyl-norleucinal; D051841:Transcription Factor RelB; D016572:Cyclosporine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus