Gene interactions and pathways from curated databases and text-mining
J Immunol 2000, PMID: 11120852

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.

Georganas, C; Liu, H; Perlman, H; Hoffmann, A; Thimmapaya, B; Pope, R M

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.

Diseases/Pathways annotated by Medline MESH: Arthritis, Rheumatoid
Document information provided by NCBI PubMed

Text Mining Data

IL-6 → IL-1ss: " 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 "

IL-6 → NF-kappaB: " 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 "

IL-8 → IL-1ss: " 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 "

IL-8 → NF-kappaB: " 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 "

IL-6 → C/EBPbeta: " 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 "

IL-6 → IL-1beta: " 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 "

IL-6 ⊣ c-Jun/AP-1: " Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8 "

IL-8 ⊣ c-Jun/AP-1: " Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8 "

C/EBPbeta → c-Jun: " 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 "

C/EBPbeta → NF-kappaB: " 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 "

c-Jun → NF-kappaB: " 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 "

IL-6 → IL-1: " 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 "

IL-6 → NF-kappaB: " 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 "

IL-6 → IL-1beta: " 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 "

IL-8 → IL-1beta: " 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 "

Manually curated Databases

No curated data.