Inhibition of IL-1beta-mediated inflammatory responses by the IkappaB alpha super-repressor in human fibroblast-like synoviocytes.
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.
Lee
Young-Rae
YR
Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
Kweon
Suc-Hyun
SH
Kwon
Kang-Beom
KB
Park
Jin-Woo
JW
Yoon
Taek-Rim
TR
Park
Byung-Hyun
BH
D000256:Adenoviridae; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054365:Chemokine CXCL5 / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000276:immunology* / Q000633:toxicity; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology*
C486263:CXCL5 protein, human; D018946:Chemokine CCL5; D054365:Chemokine CXCL5; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1