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 (K d=4.5±2.5×10−10 M). TNF-alpha did not competitively inhibit125I-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 theK d. Unstimulated FLS also expressed 2850 ± 700 TNF-alpha receptors per cells, with a singleK d consistent with the lower-affinity TNF-alpha receptor (7.4±0.2×10−10 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 theK d. Low levels of the soluble 55-kD TNF receptor were detected in FLS supernatants. IFN-gamma did not effect soluble TNF receptor production. These data are the first demonstration of IFN-gamma and TNF-alpha receptors on FLS and show that TNF-alpha and IFN-gamma increase the expression of each other's receptor. Therefore the mutual antagonism between these two cytokines must occur through a postreceptor mechanism.
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Alvaro-Gracia, J.M., Yu, C., Zvaifler, N.J. et al. 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 13, 212–218 (1993). https://doi.org/10.1007/BF00919974
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DOI: https://doi.org/10.1007/BF00919974