IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes : JAKinibs suppress the interferon response in RA-FLSs

Exp Mol Med. 2019 Jul 8;51(7):1-11. doi: 10.1038/s12276-019-0267-6.

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Azetidines / therapeutic use
  • Biomarkers / metabolism
  • Female
  • Gene Expression
  • Humans
  • Inflammation
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferons / genetics
  • Interferons / metabolism*
  • Janus Kinase Inhibitors / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Piperidines / therapeutic use
  • Pyrimidines / therapeutic use
  • Pyrroles / therapeutic use
  • Signal Transduction / drug effects*
  • Sulfonamides / therapeutic use
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Synoviocytes / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Azetidines
  • Biomarkers
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Janus Kinase Inhibitors
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • tofacitinib
  • Interferons
  • baricitinib