Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation.
OBJECTIVE
Inhibitor of nuclear factor kappaB kinase beta (IkappaB kinase beta, or IKKbeta) has emerged as a key regulator of the transcription factor nuclear factor kappaB (NF-kappaB). Since IKKbeta could have both pro- and antiinflammatory activity, we examined whether its constitutive activation was sufficient to cause a chronic inflammatory disease such as rheumatoid arthritis.


METHODS
Normal Lewis rats were evaluated for paw swelling by plethysmometry and histologic assessment after intraarticular injection of an adenoviral construct encoding the IKKbeta wild-type gene (Ad.IKKbeta-wt); controls received an adenoviral construct encoding green fluorescent protein (Ad.GFP). The rats were killed after 7 days. Additionally, rats were killed 48 hours after intraarticular injection of Ad.IKKbeta-wt or Ad.GFP for studies of IKK activity and NF-kappaB binding. For studies of the effects of inhibition of IKKbeta activity, Lewis rats were immunized with Mycobacterium tuberculosis in mineral oil. The ankle joints were injected on day 12 with an adenoviral construct encoding IKKbeta K-->M (dominant negative, IKKbeta-dn) or Ad.GFP. We evaluated paw swelling and NF-kappaB expression on day 25.


RESULTS
Intraarticular gene transfer of IKKbeta-wt into the joints of normal rats resulted in significant paw swelling and histologic evidence of synovial inflammation. Increased IKK activity was detectable in the IKKbeta-wt-injected ankle joints, coincident with enhanced NF-kappaB DNA binding activity. Intraarticular gene transfer of IKKbeta-dn significantly ameliorated the severity of adjuvant arthritis, accompanied by a significant decrease in NF-kappaB DNA expression in the joints of Ad.IKKbeta-dn-treated animals.


CONCLUSIONS
IKKbeta plays a key role in rodent synovial inflammation. Intraarticular gene therapy to inhibit IKKbeta activity represents an attractive strategy for the treatment of chronic arthritis.
Tak
P P
PP
University of California (San Diego) School of Medicine, La Jolla, USA.
Gerlag
D M
DM
Aupperle
K R
KR
van de Geest
D A
DA
Overbeek
M
M
Bennett
B L
BL
Boyle
D L
DL
Manning
A M
AM
Firestein
G S
GS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D002478:Cells, Cultured; D015316:Genetic Therapy; D005822:Genetic Vectors; D051550:I-kappa B Kinase; D008297:Male; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology*; D014162:Transfection
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase