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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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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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].”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [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
- hybrid
- doi.org
- Licence
- 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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