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Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2000 Dec 15; Vol. 165 (12), pp. 7199-206. - Publication Year :
- 2000
-
Abstract
- Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) produce IL-6 and IL-8, which contribute to inflammation and joint damage. The promoters of both cytokines possess binding sites for NF-kappaB, C/EBPbeta, and c-Jun, but the contribution of each to the regulation of IL-6 and IL-8 in RA FLS is unknown. We employed adenoviral-mediated gene delivery of a nondegradable IkappaBalpha, or dominant-negative versions of C/EBPbeta or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-kappaB activation significantly reduced the spontaneous and IL-1beta-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1ss-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPbeta modestly reduced constitutive and IL-1beta-induced IL-6 by RA FLS, but not by human dermal fibroblasts, and had no effect on IL-8. Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8. Employing gel shift assays, NF-kappaB, C/EBPbeta, and c-Jun were constitutively activated in RA FLS, but only NF-kappaB and c-Jun activity increased after IL-1beta. The reduction of cytokines by IkappaBalpha was mediated through inhibition of NF-kappaB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-kappaB was essential for IL-6 expression, because fibroblasts in which both NF-kappaB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-kappaB for the regulation of the constitutive and IL-1beta-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-kappaB as a therapeutic goal in RA.
- Subjects :
- Adenoviruses, Human genetics
Arthritis, Rheumatoid metabolism
Arthritis, Rheumatoid pathology
CCAAT-Enhancer-Binding Proteins biosynthesis
CCAAT-Enhancer-Binding Proteins metabolism
Cells, Cultured
DNA-Binding Proteins biosynthesis
DNA-Binding Proteins genetics
Dose-Response Relationship, Immunologic
Genetic Vectors immunology
Humans
Interleukin-1 pharmacology
Interleukin-6 antagonists & inhibitors
Interleukin-6 genetics
Interleukin-8 antagonists & inhibitors
Interleukin-8 genetics
NF-KappaB Inhibitor alpha
NF-kappa B metabolism
Proto-Oncogene Proteins c-jun biosynthesis
Proto-Oncogene Proteins c-jun genetics
Proto-Oncogene Proteins c-jun metabolism
Skin cytology
Skin immunology
Skin metabolism
Synovial Membrane metabolism
Synovial Membrane pathology
Transcription Factor AP-1 biosynthesis
Transcription Factor AP-1 genetics
Transcription Factor AP-1 metabolism
Transcriptional Activation immunology
Arthritis, Rheumatoid immunology
CCAAT-Enhancer-Binding Proteins physiology
Fibroblasts immunology
Fibroblasts metabolism
I-kappa B Proteins
Interleukin-6 biosynthesis
Interleukin-8 biosynthesis
NF-kappa B physiology
Proto-Oncogene Proteins c-jun physiology
Synovial Membrane immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 165
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 11120852
- Full Text :
- https://doi.org/10.4049/jimmunol.165.12.7199