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. (C) 2008 Elsevier Inc. All rights reserved.