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

• Published in: Arthritis and rheumatism Vol. 46; no. 1; pp. 31 - 41
• Main Authors: Brennan, Fionula M, Hayes, Amanda L, Ciesielski, Cathleen J, Green, Patricia, Foxwell, Brian M J, Feldmann, Marc
• Format: Journal Article
• Language: English
• Published: United States 01.01.2002
• Subjects: 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; Phosphatidylinositol 3-Kinases - antagonists & 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
• ISSN: 0004-3591

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