Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on fibroblast-like synoviocytes: paradoxical induction of IFN-gamma and TNF-alpha receptor expression.
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)
UCSD Medical Center 92103.
J M
JM
Alvaro-Gracia
C
C
Yu
N J
NJ
Zvaifler
G S
GS
Firestein
D001172:Arthritis, Rheumatoid / Q000276:immunology; D001667:Binding, Competitive; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010003:Osteoarthritis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D011956:Receptors, Cell Surface; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma