Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumor necrosis factor alpha production in rheumatoid arthritis

Arthritis Rheum. 2002 Jan;46(1):31-41. doi: 10.1002/1529-0131(200201)46:1<31::AID-ART10029>3.0.CO;2-5.


Objective: To investigate the mechanism that leads to the spontaneous production of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) synovial tissue.

Methods: Normal blood monocytes were cocultured either with fixed activated T cells generated from normal blood or RA synovial T cells purified from synovium. TNFalpha production was measured in supernatants from these cocultures following blockade of the transcription factor nuclear factor kappaB (NF-kappaB) using adenoviral transfer of the inhibitor of NF-kappaB kinase alpha into the responding monocytes, or blockade of phosphatidylinositol 3-kinase (PI 3-kinase) using the inhibitory drugs wortmannin or LY294002. TNFalpha production was measured by enzyme-linked immunosorbent assay.

Results: TNFalpha production in synovial tissue from patients with RA but not osteoarthritis was found to be T cell dependent. The RA synovial joint T cells resembled normal T cells that had been activated for 8 days using a cocktail of cytokines. These T cells, designated Tck (cytokine-activated T cells), and RA synovial T cells both induced TNFalpha production in resting monocytes in a cell-contact-dependent manner, which was abrogated by blockage of the transcription factor NF-kappaB but augmented if PI 3-kinase was inhibited. Normal blood T cells activated conventionally via the T cell receptor with crosslinked anti-CD3 antibody resulted in TNFalpha production from monocytes; this was unaffected by NF-kappaB blockade, but was inhibited in the presence of PI 3-kinase-blocking drugs.

Conclusion: These data provide strong evidence for the importance of T cells in inducing TNFalpha in chronic inflammatory rheumatoid tissue, and give insight into the mechanism whereby these T cells are activated in vivo. Furthermore, they indicate that production of TNFalpha in pathologic tissue is regulated differently from physiologic antigen-dependent TNFalpha production, which raises the possibility that selective inhibitors of TNFalpha in disease may be developed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Androstadienes / pharmacology
  • Arthritis, Rheumatoid / immunology*
  • CD3 Complex / immunology
  • Cell Communication / immunology
  • Chromones / pharmacology
  • Coculture Techniques
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Genetic Vectors
  • Humans
  • I-kappa B Proteins*
  • Immunophenotyping
  • Lymphocyte Activation / immunology*
  • Macrophages / cytology
  • Macrophages / immunology
  • Monocytes / cytology
  • Monocytes / immunology
  • Morpholines / pharmacology
  • NF-KappaB Inhibitor alpha
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction / immunology
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Wortmannin


  • Androstadienes
  • CD3 Complex
  • Chromones
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Morpholines
  • NFKBIA protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Wortmannin