NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint.
The transcription factor NF-kappaB is a pivotal regulator of inflammatory responses. While the activation of NF-kappaB in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-kappaB in animal models of RA. We demonstrate that in vitro, NF-kappaB controlled expression of numerous inflammatory molecules in synoviocytes and protected cells against tumor necrosis factor alpha (TNFalpha) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-kappaB was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-kappaB by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IkappaBalpha profoundly enhanced apoptosis in the synovium of rats with SCW- and pristane-induced arthritis. This indicated that the activation of NF-kappaB protected the cells in the synovium against apoptosis and thus provided the potential link between inflammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-kappaB. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-kappaB.
Miagkov
A V
AV
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Kovalenko
D V
DV
Brown
C E
CE
Didsbury
J R
JR
Cogswell
J P
JP
Stimpson
S A
SA
Baldwin
A S
AS
Makarov
S S
SS
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D007596:Joints / Q000276:immunology* / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D051381:Rats
D016328:NF-kappa B