title: Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis.
abstract: The transcription factor NF-kappaB activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-kappaB exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein IkappaB is degraded by the ubiquitin-proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-kappaB. This suppression should therefore decrease transcription of many genes encoding proinflammatory proteins and should ultimately have an anti-inflammatory effect. To this end, a series of peptide boronic acid inhibitors of the proteasome, exemplified herein by PS-341, were developed. The proteasome is the large multimeric protease that catalyzes the final proteolytic step of the ubiquitin-proteasome pathway. PS-341, a potent, competitive inhibitor of the proteasome, readily entered cells and inhibited the activation of NF-kappaB and the subsequent transcription of genes that are regulated by NF-kappaB. Significantly, PS-341 displayed similar effects in vivo. Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats. The attenuation of inflammation in this model was associated with an inhibition of IkappaBalpha degradation and NF-kappaB-dependent gene expression. These experiments clearly demonstrate that the ubiquitin-proteasome pathway and NF-kappaB play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.
authors.affiliation: ProScript, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: Palombella
authors.forename: E M
authors.initials: EM
authors.lastname: Conner
authors.forename: J W
authors.initials: JW
authors.lastname: Fuseler
authors.forename: A
authors.initials: A
authors.lastname: Destree
authors.forename: J M
authors.initials: JM
authors.lastname: Davis
authors.forename: F S
authors.initials: FS
authors.lastname: Laroux
authors.forename: R E
authors.initials: RE
authors.lastname: Wolf
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Brand
authors.forename: P J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: D
authors.initials: D
authors.lastname: Lazarus
authors.forename: T
authors.initials: T
authors.lastname: McCormack
authors.forename: L
authors.initials: L
authors.lastname: Parent
authors.forename: R
authors.initials: R
authors.lastname: Stein
authors.forename: J
authors.initials: J
authors.lastname: Adams
authors.forename: M B
authors.initials: MB
authors.lastname: Grisham
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D002473:Cell Wall / Q000276:immunology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011917:Rats, Inbred Lew; D013291:Streptococcus / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism; D014471:Umbilical Veins
chemical_list: D015815:Cell Adhesion Molecules; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D009097:Multienzyme Complexes; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D009569:Nitric Oxide; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex