ArticleArthritis research & therapy2016
A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator.
Article in Arthritis research & therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Transethnic meta-analysis identifiesAnnals of the rheumatic diseases · 2017Pooled it
- Systemic Sclerosis in Kazakh Patients: A Preliminary Case-Control Immunogenetic Profiling Study.Pathophysiology : the official journal of the International Society for Pathophysiology · 2025Article
- A20 mRNA therapeutics ameliorate systemic sclerosis by suppressing TRAF-6/NF-KB signaling and DREAM expression and exerting antifibrotic effects.Frontiers in immunology · 2025Article
- LPANano research · 2024Article
- Immunogenetics of Systemic Sclerosis.Genes · 2024Review
- Article
- A20 Attenuates the Fibrotic Response in the Trabecular Meshwork.International journal of molecular sciences · 2022Article
- Inhibition of miR-23b-3p Ameliorates Scar-Like Phenotypes of Keloid Fibroblasts by Facilitating A20 Expression.Clinical, cosmetic and investigational dermatology · 2022Article
- Screening and identification of potential biomarkers and therapeutic targets for systemic sclerosis-associated interstitial lung disease.Archives of rheumatology · 2021Article
- Down-regulation of A20 promotes immune escape of lung adenocarcinomas.Science translational medicine · 2021Article
- Updates on genetics in systemic sclerosis.Inflammation and regeneration · 2021Review
- The Ubiquitin System and A20: Implications in Health and Disease.Journal of dental research · 2021Review
- Role of adipokines in systemic sclerosis pathogenesis.European journal of rheumatology · 2020Review
- Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β.Rheumatology (Oxford, England) · 2019Article
- TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling.Journal of immunology research · 2018Review
- Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma.Advances in wound care · 2017Review
- A20 Attenuates Liver Fibrosis in NAFLD and Inhibits Inflammation Responses.Inflammation · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe ubiquitin-editing cytosolic enzyme A20, the major negative regulator of toll-like receptor (TLR)-mediated cellular inflammatory responses, has tight genetic linkage with systemic sclerosis (SSc). Because recent studies implicate endogenous ligand-driven TLR signaling in SSc pathogenesis, we sought to investigate the regulation, role and mechanism of action of A20 in skin fibroblasts.
methodA20 expression and the effects of forced A20 expression or siRNA-mediated A20 knockdown on fibrotic responses induced by transforming growth factor-ß (TGF-ß) were evaluated was evaluated in explanted human skin fibroblasts. Additionally, A20 regulation by TGF-ß, and by adiponectin, a pleiotropic adipokine with anti-fibrotic activity, was evaluated.
resultsIn normal fibroblasts, TGF-ß induced sustained downregulation of A20, and abrogated its TLR4-dependent induction. Forced expression of A20 aborted the stimulation of collagen gene expression and myofibroblast transformation induced by TGF-ß, and disrupted canonical Smad signaling and Smad-dependent transcriptional responses. Conversely, siRNA-mediated knockdown of A20 enhanced the amplitude of fibrotic responses elicited by TGF-ß. Adiponectin, previously shown to block TLR-dependent fibrotic responses, elicited rapid and sustained increase in A20 accumulation in fibroblasts.
conclusionThese results identify the ubiquitin-editing enzyme A20 as a novel endogenous mechanism for negative regulation of fibrotic response intensity. Systemic sclerosis-associated genetic variants of A20 that cause impaired A20 expression or function, combined with direct suppression of A20 by TGF-ß within the fibrotic milieu, might play a significant functional role in persistence of fibrotic responses, while pharmacological augmentation of A20 inhibitory pathway activity might represent a novel therapeutic strategy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.