Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis.
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.
Palombella
V J
VJ
ProScript, Inc., 38 Sidney Street, Cambridge, MA 02139, USA.
Conner
E M
EM
Fuseler
J W
JW
Destree
A
A
Davis
J M
JM
Laroux
F S
FS
Wolf
R E
RE
Huang
J
J
Brand
S
S
Elliott
P J
PJ
Lazarus
D
D
McCormack
T
T
Parent
L
L
Stein
R
R
Adams
J
J
Grisham
M B
MB
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
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