Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy.
OBJECTIVE
In both rheumatoid arthritis and collagen-induced arthritis (CIA), the nuclear factor kappaB (NF-kappaB) transcription factor plays a pivotal role in the coordinated transactivation of many cytokines related to pathogenesis. This study investigated whether synthetic double-stranded DNA that show a high affinity for NF-kappaB could be introduced in vivo as "decoy" cis elements to bind the transcription factor and block the activation of such proinflammatory cytokine genes as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha), and thus suppress the severity of joint destruction.


METHODS
NF-kappaB decoy oligonucleotides (ODN) were introduced by an intraarticular injection into the bilateral hind ankle joints of CIA rats using the hemagglutinating virus of Japan (HVJ)-liposome method. Joint destruction was evaluated by histology and radiography. IL-1 and TNFalpha levels were assessed by enzyme-linked immunosorbent assay and Northern blot analysis.


RESULTS
Using the HVJ-liposome method, the presence of fluorescein isothiocyanate-labeled ODN in the synovium was confirmed until 28 days after intraarticular injection. In vivo transfection of NF-kappaB decoy ODN by an intraarticular injection into CIA rats decreased the severity of hind-paw swelling. Histologic and radiographic studies showed a marked suppression of joint destruction treated by NF-kappaB decoy ODN transfection. This treatment method also suppressed the production of IL-1 and TNFalpha in the synovium of arthritic joints.


CONCLUSIONS
The present results demonstrate that administration of NF-kappaB decoy ODN in arthritic joints of rats with CIA led to an amelioration of arthritis. These findings suggest that intraarticular transfection of NF-kappaB decoy ODN may provide a useful therapeutic approach for the treatment of inflammatory arthritis.
Tomita
T
T
Department of Orthopaedic Surgery, Osaka University Medical School, Suita, Japan.
Takeuchi
E
E
Tomita
N
N
Morishita
R
R
Kaneko
M
M
Yamamoto
K
K
Nakase
T
T
Seki
H
H
Kato
K
K
Kaneda
Y
Y
Ochi
T
T
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate; D015870:Gene Expression; D015316:Genetic Therapy; D007270:Injections, Intra-Articular; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology; D008081:Liposomes; D016328:NF-kappa B / Q000008:administration & dosage*; D009841:Oligonucleotides / Q000008:administration & dosage*; D051381:Rats; D018108:Respirovirus / Q000235:genetics; D013583:Synovial Membrane / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
D007375:Interleukin-1; D008081:Liposomes; D016328:NF-kappa B; D009841:Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate