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Epigenetic DNA methylation of EBI3 modulates human interleukin-35 formation via NFkB signaling
- Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNF alpha led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NF kappa B signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESIMS/MS analysis of DAC/TNF alpha-treated HCEC identified IL-12p35 asUlcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNF alpha led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NF kappa B signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESIMS/MS analysis of DAC/TNF alpha-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNF alpha-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.…
Author details: | Alexandra Nicole WetzelGND, Bettina ScholtkaORCiD, Fabian SchumacherORCiDGND, Harshadrai Manilal RawelORCiDGND, Birte GeisendörferGND, Burkhard KleuserORCiDGND |
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DOI: | https://doi.org/10.3390/ijms22105329 |
ISSN: | 1422-0067 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/34069352 |
Title of parent work (English): | International journal of molecular sciences |
Subtitle (English): | a promising therapeutic option in ulcerative colitis |
Publisher: | MDPI |
Place of publishing: | Basel |
Publication type: | Article |
Language: | English |
Date of first publication: | 2021/05/19 |
Publication year: | 2021 |
Release date: | 2023/07/14 |
Tag: | DNMT inhibitor; EBI3; TNF alpha; Ulcerative colitis; decitabine; inhibitory cytokines; interleukin-35 |
Volume: | 22 |
Issue: | 10 |
Article number: | 5329 |
Number of pages: | 21 |
Funding institution: | DEUTSCHE FORSCHUNGSGEMEINSCHAFT German Research Foundation (DFG) [GRK 2581] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie | |
Peer review: | Referiert |
Publishing method: | Open Access / Gold Open-Access |
DOAJ gelistet | |
License (German): | CC-BY - Namensnennung 4.0 International |