Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts

Oncogene. 2003 Oct 30;22(49):7796-803. doi: 10.1038/sj.onc.1206965.


Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with abberrant proliferation of synoviocytes. In order to explore the characteristics of rheumatoid synovial fibroblasts (RSF), we performed the comparative gene expression profile analysis between RSF and normal synovial fibroblasts (NSF) upon tumor necrosis factor (TNF) stimulation. As an initial screening for the genes preferentially induced by TNF in RSF compared with NSF, we have adopted a cDNA array containing well-defined sets of genes responsible for cell growth, cell fate determination, and cellular invasiveness. Differentially expressed genes of interest were confirmed using real-time RT-PCR. We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 and Notch-4 antibody. TNF induced the nuclear translocation of Notch intracellular domain in RSF, indicating the elicitation of the Notch signaling. Notch-1, Notch-4, and Jagged-2 proteins were also detected in the developing synovium of mouse embryo. Thus, RSF may have re-acquired the primordial phenotype, accounting for the hyperproliferation and aggressive invasiveness, exhibiting tumor-like phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Embryo, Mammalian / metabolism
  • Female
  • Fibroblasts / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Jagged-2 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred ICR
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, Notch1
  • Receptor, Notch4
  • Receptors, Cell Surface*
  • Receptors, Notch
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synovial Membrane / cytology
  • Transcription Factors*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Carrier Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG2 protein, human
  • Jag2 protein, mouse
  • Jagged-2 Protein
  • Membrane Proteins
  • NOTCH1 protein, human
  • NOTCH4 protein, human
  • Notch1 protein, mouse
  • Proto-Oncogene Proteins
  • Receptor, Notch1
  • Receptor, Notch4
  • Receptors, Cell Surface
  • Receptors, Notch
  • Transcription Factors
  • Tumor Necrosis Factor-alpha