Inhibition of IL-1{beta}-mediated inflammatory responses by the I{kappa}B{alpha} super-repressor in human fibroblast-like synoviocytes

The IL-1{beta}-NF-{kappa}B axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1{beta}-induced toxicity...

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Published inBiochemical and biophysical research communications Vol. 378; no. 1
Main Authors Lee, Young-Rae, Kweon, Suc-Hyun, Kwon, Kang-Beom, Park, Jin-Woo, Yoon, Taek-Rim, Park, Byung-Hyun
Format Journal Article
LanguageEnglish
Published United States 02.01.2009
Subjects
60 APPLIED LIFE SCIENCES
ADENOVIRUS
CELL PROLIFERATION
DNA
FIBROBLASTS
INFLAMMATION
INHIBITION
JOINTS
MUTANTS
PATHOGENESIS
RHEUMATIC DISEASES
TOXICITY
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Summary:The IL-1{beta}-NF-{kappa}B axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1{beta}-induced toxicity by an overexpressing I{kappa}B super-repressor. Infection of FLS with Ad-I{kappa}B{alpha} (S32A, S36A), an adenovirus-containing mutant I{kappa}B{alpha}, inhibited IL-1{beta}-induced nuclear translocation and DNA binding of NF-{kappa}B. In addition, Ad-I{kappa}B{alpha} (S32A, S36A) prevented IL-1{beta}-induced inflammatory responses; namely, the production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3. Finally, increased cellular proliferation of FLS after IL-1{beta} treatment was significantly reduced by Ad-I{kappa}B{alpha} (S32A, S36A). However, Ad-I{kappa}B{beta} (S19A, S23A), the I{kappa}B{beta} mutant, was not effective in preventing IL-1{beta} toxicity. These results suggest that inhibition of I{kappa}B{alpha} degradation is a potential target for the prevention of joint destruction in patients with RA.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.11.002