Cytokines in chronic inflammatory arthritis. V. 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

J Clin Invest. 1990 Dec;86(6):1790-8. doi: 10.1172/JCI114908.


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 fibroblast-like RA synoviocytes. The following recombinant cytokines were used: IL-1 beta, 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-1 beta and TNF-alpha induced collagenase production (from less than 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arthritis, Rheumatoid / physiopathology*
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / physiology*
  • Gene Expression / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • HLA-DQ Antigens / metabolism
  • HLA-DR Antigens / metabolism
  • Humans
  • In Vitro Techniques
  • Indomethacin / pharmacology
  • Interferon-gamma / physiology
  • Microbial Collagenase / biosynthesis
  • Prostaglandins / physiology
  • RNA, Messenger / genetics
  • Synovial Membrane / pathology
  • Synovial Membrane / physiopathology*
  • Time Factors
  • Tumor Necrosis Factor-alpha / physiology


  • Cytokines
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • Prostaglandins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Microbial Collagenase
  • Indomethacin