Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on fibroblast-like synoviocytes: paradoxical induction of IFN-gamma and TNF-alpha receptor expression

J Clin Immunol. 1993 May;13(3):212-8. doi: 10.1007/BF00919974.

Abstract

We recently described mutual antagonism between IFN-gamma and TNF-alpha on human fibroblast-like synoviocytes (FLS). TNF-alpha inhibits IFN-gamma-induced HLA-DR expression and IFN-gamma blocks TNF-alpha-dependent synoviocyte proliferation, collagenase production, and GM-CSF secretion. To study the mechanism of antagonism we have analyzed the effect these factors on the expression of cytokine surface receptors. 125I-Labeled cytokine binding was measured on cultured FLS and the results were analyzed by Scatchard plots. Unstimulated synoviocytes expressed 9300 +/- 1560 IFN-gamma binding sites per cell. A single class of high-affinity receptor was observed (Kd = 4.5 +/- 2.5 x 10(-10) M). TNF-alpha did not competitively inhibit 125I-IFN-gamma binding. When FLS were incubated with TNF-alpha (100 ng/ml), there was a paradoxical 49.5 +/- 5.6% increase in the number of binding sites for IFN-gamma (P = 0.001), with no change in the Kd. Unstimulated FLS also expressed 2850 +/- 700 TNF-alpha receptors per cells, with a single Kd consistent with the lower-affinity TNF-alpha receptor (7.4 +/- 0.2 x 10(-10) M). IFN-gamma did not directly interfere with TNF-alpha binding. Preincubation of FLS with 100 U/ml of IFN-gamma resulted in a 28.9 +/- 9.0% increase in TNF-alpha receptor expression (P < 0.008), with no change in the Kd. Low levels of the soluble 55-kD TNF receptor were detected in FLS supernatants. IFN-gamma did not effect soluble TNF receptor production.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

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

MeSH terms

  • Arthritis, Rheumatoid / immunology
  • Binding, Competitive
  • Cells, Cultured
  • Fibroblasts / immunology
  • Humans
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / pharmacology
  • Osteoarthritis / immunology
  • Receptors, Cell Surface / metabolism*
  • Receptors, Interferon / metabolism*
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Synovial Fluid / drug effects
  • Synovial Fluid / immunology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Receptors, Cell Surface
  • Receptors, Interferon
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma