Cited by 69Rheumatoid Arthritis Research and TherapiesNF-κB Signaling PathwaysCytokine Signaling Pathways and Interactions

Transcriptional Roles of CCAAT/Enhancer Binding Protein-β, Nuclear Factor-κB, and C-promoter Binding Factor 1 in Interleukin (IL)-1β-induced IL-6 Synthesis by Human Rheumatoid Fibroblast-like Synoviocytes

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Miyazawa, Keiji, Mori, Akio, Yamamoto, Kazuhiko, Okudaira, Hirokazu·1998·Journal of Biological Chemistry

Abstract

The involvement of interleukin (IL)-6 in the pathogenesis of rheumatoid arthritis (RA) has been recently demonstrated. IL-1beta stimulated rheumatoid fibroblast-like synoviocytes (FLSs) to produce IL-6 in a concentration- and time-dependent manner. In the present study we investigated how the IL-6 promoter is transcriptionally regulated in rheumatoid FLSs in response to a physiologically relevant mediator of inflammation, IL-1beta. Deletion analysis showed that the IL-6 promoter is regulated by two positive elements (located at -159 to -142 base pairs (bp) and -77 to -59 bp). Electrophoretic mobility shift assays revealed that CCAAT/enhancer binding protein-beta (C/EBPbeta) binding to nucleotides -159 to -142 bp was constitutively present. The probe corresponding to nucleotides -77 to -59 bp gave three positive bands. The two slower migrating bands were induced by IL-1beta and comprised an nuclear factor (NF)-kappaB p50/p65 heterodimer and a p65/p65 homodimer. The faster migrating band was constitutively expressed and identified as Epstein-Barr virus C-promoter binding factor 1, CBF1. Site-specific mutagenesis analysis demonstrated that the NF-kappaB and CBF1 binding elements regulated inducible activity of the IL-6 promoter in response to IL-1beta stimulation, whereas the C/EBPbeta binding element mainly regulated basal activity. We also provide the first evidence that CBF1 functions as a positive regulator of human IL-6 gene transcription.

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Crossref · 10.1074/jbc.273.13.7620

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  • IL-6 induction by LPS in hepatocytes is either occurring downstream of an alternative NFκB pathway or occurs via a completely separate mechanism.

    “This suggests that IL-6 induction by LPS is either occurring downstream of an alternative NFκB pathway or occurs via a completely separate mechanism [28], [29].”

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Authors
Miyazawa, K., Mori, A., Yamamoto, K., & Okudaira, H.
Affiliations
The University of Tokyo (JP)
Corresponding author
Miyazawa, Keiji
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1998-03
Volume
273
Issue
13
Pages
7620-7627
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1995124863
Cited by
69
References
49
Citations by year
2024: 1 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 1
FWCI
4.30
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, IL-6 promoter, rheumatoid arthritis, synovial fibroblasts, IL-1β, C/EBPβ, NF-κB, CBF1, transcriptional regulation, rheumatoid synovitis, promoter elements, positive transcriptional regulation
MeSH terms
Arthritis, Rheumatoid, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Interleukin-1, Nuclear Proteins, Promoter Regions, Genetic, Recombinant Proteins, Synovial Membrane, Transcription Factors, Transcription, Genetic, Interleukin-6, NF-kappa B, CCAAT-Enhancer-Binding Proteins, Immunoglobulin J Recombination Signal Sequence-Binding Protein

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