ArticleMolecular immunology2019
SKI and SMAD4 are essential for IL-21-induced Th17 differentiation.
Article in Molecular immunology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- SKI is critical to counter TGF-β signaling to promote T cell function and autoimmunity.Science advances · 2026Article
- Association Between the Expression of T Helper Type 17 Cell-Related Cytokines and Valve Damage in Rheumatic Heart Disease.Molecular biotechnology · 2025Article
- DNA 5-Hydroxymethylcytosine Landscape and Transcriptional Profile Highlight the TUBB4B-Mediated Th17/Th1/Treg Imbalance in Behçet's Uveitis.Investigative ophthalmology & visual science · 2025Article
- Systemic dysregulation of the gut microenvironment plays a pivotal role in the onset and progression of inflammatory bowel disease.Frontiers in immunology · 2025Review
- Article
- Analysis of alpha-1-antitrypsin (AAT)-regulated, glucocorticoid receptor-dependent genes in macrophages reveals a novel host defense function of AAT.Physiological reports · 2024Article
- Therapeutic potential of interleukin-21 in cancer.Frontiers in immunology · 2024Review
- Context-dependent TGFβ family signalling in cell fate regulation.Nature reviews. Molecular cell biology · 2023Review
- Novel Probiotic BacteriumMicroorganisms · 2023Article
- Intricacies of TGF-β signaling in Treg and Th17 cell biology.Cellular & molecular immunology · 2023Review
- Smad4 and p53 synergize in suppressing autochthonous intestinal cancer.Cancer medicine · 2022Article
- Mannan-Binding Lectin Regulates the Th17/Treg Axis Through JAK/STAT and TGF-β/SMAD Signaling AgainstJournal of inflammation research · 2022Article
- Article
- Consequences of Mutations and Abnormal Expression of SMAD4 in Tumors and T Cells.OncoTargets and therapy · 2021Review
- Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis.Journal of immunology research · 2021Review
- Article
- T Cells in Fibrosis and Fibrotic Diseases.Frontiers in immunology · 2020Review
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
Th17 cells are essential for the pathogenesis of inflammatory and autoimmune diseases. In the presence of TGF-β, the differentiation of Th17 cells can be induced by inflammatory cytokines, especially IL-6, which is mainly produced by antigen presenting cells (APCs); or IL-21, which is derived from T cells. IL-21 is required for IL-6-induced Th17 cell differentiation. However, the key regulators and underlying mechanisms for IL-21-induced Th17 differentiation is still elusive. Here we show that SMAD4 is a key regulator in IL-21-induced Th17 differentiation. SMAD4 deficient naïve T cells can differentiate into Th17 cells in the absence of TGF-β signaling, and these Th17 cells are pathogenic during EAE. SMAD4 represses Rorc mRNA transcription to constrain IL-21-induced Th17 differentiation in the absence of TGF-β signaling. While in the presence of TGF-β, SMAD4 losses its suppressive ability due to the degradation of SKI. Mutation of Y429A or A432E on SMAD4 disrupts the interaction of SKI from SMAD4 and eliminates SMAD4 mediated suppression of Th17 differentiation. SMAD4 is indispensable for SKI binding to Rorc promoter region to regulate Th17 differentiation. Moreover, activin can induce Th17 differentiation in combination with IL-21, and the process is also subjected to the control of SKI and SMAD4. This study therefore elucidates critical mechanism for IL-21-induced Th17 differentiation to indicate SKI and SMAD4 as potential therapeutic targets for treating autoimmune diseases.
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