Effective adenoviral transfer of IkappaBalpha into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-kappaB dependent.
OBJECTIVE
To determine whether, in human fibroblasts and chondrosarcoma cells, the regulation of interleukins (IL)-6, 8, and 11 and matrix metalloproteinases (MMP)-1, 3, and 13, and their tissue inhibitor TIMP-1, depends on the transcription factor nuclear factor-kappaB (NF-kappaB).


METHODS
Fibroblasts and chondrosarcoma cells were effectively infected with an adenovirus encoding human IkappaBalpha, and inhibition of NF-kappaB function was observed. The induction of MMP and IL-6, 8, and 11 by various stimuli was assessed by ELISA.


RESULTS
The induction of IL-6 and IL-8 clearly depended on NF-kappaB in both fibroblasts and chondrosarcoma cells, irrespective of stimulus, but IkappaBalpha overexpression had little effect on IL-11. MMP-1, -3, and -13 were also inhibited, but TIMP-1 was unaffected.


CONCLUSIONS
NF-kappaB appears to play an important and selective role in MMP induction in human fibroblasts and chondrosarcoma cells. This suggests there are NF-kappaB dependent mechanisms of cartilage destruction in rheumatoid arthritis, and supports the concept that there are similarities in the regulation of inflammatory and destructive pathways in that disease.
Bondeson
J
J
Kennedy Institute of Rheumatology, London, UK.
Brennan
F
F
Foxwell
B
B
Feldmann
M
M
D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000503:physiopathology; D002813:Chondrosarcoma / Q000201:enzymology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000201:enzymology / Q000235:genetics*; D007375:Interleukin-1 / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics*; D010703:Phorbol Esters / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D020782:Matrix Metalloproteinases