Inhibition of IL-1β-mediated inflammatory responses by the IκBα super-repressor in human fibroblast-like synoviocytes

The IL-1β-NF-κB 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-1β-induced toxicity by an overexpressing IκB super-repressor. Infection of FLS with Ad-IκBα (S32A, S36A), an adenovirus-containing mutant IκBα, inhibited IL-1β-induced nuclear translocation and DNA binding of NF-κB. In addition, Ad-IκBα (S32A, S36A) prevented IL-1β-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-1β treatment was significantly reduced by Ad-IκBα (S32A, S36A). However, Ad-IκBβ (S19A, S23A), the IκBβ mutant, was not effective in preventing IL-1β toxicity. These results suggest that inhibition of IκBα degradation is a potential target for the prevention of joint destruction in patients with RA.