ArticleCell communication and signaling : CCS2020
β-Catenin and TCFs/LEF signaling discordantly regulate IL-6 expression in astrocytes.
Article in Cell communication and signaling : CCS, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 41 citations in OpenAlex.
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- Targeting a macrophage stemness factor to mitigate diseases post respiratory viral infection.bioRxiv : the preprint server for biology · 2025Article
- SARS-CoV-2 Infection Influences Wnt/β-Catenin Pathway Components in Astrocytes.Pathogens (Basel, Switzerland) · 2025Article
- Solid stress compression enhances breast cancer cell migration through the upregulation of Interleukin-6.Frontiers in cell and developmental biology · 2025Article
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- Exosomal circ-AHCY promotes glioblastoma cell growth via Wnt/β-catenin signaling pathway.Annals of clinical and translational neurology · 2023Article
- Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer.British journal of cancer · 2023Article
- DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients.Epigenetics · 2022Article
- Reactive and Senescent Astroglial Phenotypes as Hallmarks of Brain Pathologies.International journal of molecular sciences · 2022Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe Wnt/β-catenin signaling pathway is a prolific regulator of cell-to-cell communication and gene expression. Canonical Wnt/β-catenin signaling involves partnering of β-catenin with members of the TCF/LEF family of transcription factors (TCF1, TCF3, TCF4, LEF1) to regulate gene expression. IL-6 is a key cytokine involved in inflammation and is particularly a hallmark of inflammation in the brain. Astrocytes, specialized glial cells in the brain, secrete IL-6. How astrocytes regulate IL-6 expression is not entirely clear, although in other cells NFκB and C/EBP pathways play a role. We evaluated here the interface between β-catenin, TCFs/LEF and C/EBP and NF-κB in relation to IL-6 gene regulation in astrocytes.
methodsWe performed molecular loss and/or gain of function studies of β-catenin, TCF/LEF, NFκB, and C/EBP to assess IL-6 regulation in human astrocytes. Specifically, siRNA mediated target gene knockdown, cDNA over expression of target gene, and pharmacological agents for regulation of target proteins were used. IL-6 levels was evaluated by real time quantitative PCR and ELISA. We also cloned the IL-6 promoter under a firefly luciferase reporter and used bioinformatics, site directed mutagenesis, and chromatin immunoprecipitation to probe the interaction between β-catenin/TCFs/LEFs and IL-6 promoter activity.
resultsβ-catenin binds to TCF/LEF to inhibits IL-6 while TCFs/LEF induce IL-6 transcription through interaction with ATF-2/SMADs. β-catenin independent of TCFs/LEF positively regulates C/EBP and NF-κB, which in turn activate IL-6 expression. The IL-6 promoter has two putative regions for TCFs/LEF binding, a proximal site located at -91 nt and a distal site at -948 nt from the transcription start site, both required for TCF/LEF induction of IL-6 independent of β-catenin.
conclusionIL-6 regulation in human astrocytes engages a discordant interaction between β-catenin and TCF/LEF. These findings are intriguing given that no role for β-catenin nor TCFs/LEF to date is associated with IL-6 regulation and suggest that β-catenin expression in astrocytes is a critical regulator of anti-inflammatory responses and its disruption can potentially mediate persistent neuroinflammation. Video Abstract.
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