CYTOKINES IN CHRONIC INFLAMMATORY ARTHRITIS .5. MUTUAL ANTAGONISM BETWEEN INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA ON HLA-DR EXPRESSION, PROLIFERATION, COLLAGENASE PRODUCTION, AND GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR PRODUCTION BY RHEUMATOID-ARTHRITIS SYNOVIOCYTES

The effects of a broad array of cytokines, individually and in combination, were determined on separate functions (proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor [GM-CSF] production) and phenotype (expression of class II MHC antigens) of cultured fibroblastlike RA synoviocytes. The following recombinant cytokines were used: IL-1beta, IL-2, IL-3, IL-4, IFN-gamma, tumor necrosis factor (TNF)-alpha, GM-CSF, and macrophage colony-stimulating factor (M-CSF). Only IFN-gamma induced HLA-DR (but not HLA-DQ) expression. TNF-alpha inhibited IFN-gamma-mediated HLA-DR expression (46.7±4.1% inhibition) and HLA-DR mRNA accumulation. This inhibitory effect was also observed in osteoarthritis synoviocytes. Only TNF-alpha and IL-1 increased synoviocyte proliferation (stimulation index 3.60±1.03 and 2.31±0.46, respectively). IFN-gamma (but none of the other cytokines) inhibited TNF-alpha-induced proliferation (70±14% inhibition) without affecting the activity of IL-1. Only IL-1beta and TNF-alpha induced collagenase production (from < 0.10 U/ml to 1.10±0.15 and 0.72±0.24, respectively). IFN-gamma decreased TNF-alpha-mediated collagenase production (69±19% inhibition) and GM-CSF production but had no effect on the action of IL-1. These data demonstrate mutual antagonism between IFN-gamma and TNF-alpha on fibroblast-like synoviocytes and suggest a novel homeostatic control mechanism that might be defective in RA where very little IFN-gamma is produced.