Inhibition of IL-1beta-mediated inflammatory responses by the IkappaB alpha super-repressor in human fibroblast-like synoviocytes

Biochem Biophys Res Commun. 2009 Jan 2;378(1):90-4. doi: 10.1016/j.bbrc.2008.11.002. Epub 2008 Nov 11.

Abstract

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

MeSH terms

  • Adenoviridae
  • Arthritis, Rheumatoid / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Chemokine CCL5 / biosynthesis
  • Chemokine CXCL5 / biosynthesis
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Fibroblasts / pathology
  • Humans
  • I-kappa B Proteins / biosynthesis*
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / toxicity
  • Matrix Metalloproteinase 1 / biosynthesis
  • Matrix Metalloproteinase 3 / biosynthesis
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Synovial Fluid / cytology
  • Synovial Fluid / immunology*

Substances

  • CXCL5 protein, human
  • Chemokine CCL5
  • Chemokine CXCL5
  • I-kappa B Proteins
  • Interleukin-1beta
  • NF-kappa B
  • NFKBIA protein, human
  • NF-KappaB Inhibitor alpha
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1