A20 suppresses canonical Smad-dependent fibroblast activation: novel function for an endogenous inflammatory modulator.

Academic Article


  • BACKGROUND: The 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. METHOD: A20 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. RESULTS: In 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. CONCLUSION: These 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.
  • Authors

    Published In

  • Arthritis Research  Journal
  • Keywords

  • A20, Fibrosis, IL-6, LPS, Systemic sclerosis, TGF-ß, TLR4, TNFAIP3, Type I collagen, adiponectin, Blotting, Western, Cells, Cultured, Fibroblasts, Fibrosis, Fluorescent Antibody Technique, Gene Knockdown Techniques, Humans, Microscopy, Confocal, Polymerase Chain Reaction, Scleroderma, Systemic, Signal Transduction, Skin, Smad Proteins, Transforming Growth Factor beta, Tumor Necrosis Factor alpha-Induced Protein 3
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9183320
  • Author List

  • Bhattacharyya S; Wang W; Graham LVD; Varga J
  • Start Page

  • 216
  • Volume

  • 18
  • Issue

  • 1