Synergistic, additive, and antagonistic effects of interleukin-1 beta, tumor necrosis factor alpha, and gamma-interferon on prostaglandin E, hyaluronic acid, and collagenase production by cultured synovial fibroblasts.
The effects of binary combinations of the recombinant human cytokines, interleukin-1 beta (rHuIL-1 beta), tumor necrosis factor alpha (rHuTNF alpha), and gamma-interferon (rHu gamma-IFN) on the production of prostaglandin E (PGE), hyaluronic acid (HA), and collagenase by human synovial fibroblasts in culture were investigated. All 3 were stimulated by rHuIL-1 beta and rHuTNF alpha alone, but not by rHu gamma-IFN. Stimulation with rHuIL-1 beta and rHuTNF alpha occurred at femtomolar and picomolar concentrations, respectively, and maximal stimulation by rHuIL-1 beta was several times greater than that by rHuTNF alpha. Stimulation of PGE and collagenase production with rHuIL-1 beta or rHuTNF alpha was depressed by rHu gamma-IFN, depending on the concentration used. In contrast, stimulation of HA production with rHuIL-1 beta or rHuTNF alpha was unaffected or increased somewhat with rHu gamma-IFN. Combinations of rHuIL-1 beta or rHuTNF alpha had marked synergistic effects on PGE and collagenase production. However, when rHuIL-1 beta effects were maximal, rHuTNF alpha had an additive effect. These cytokines had only additive effects on HA production, however, and when rHuIL-1 beta effects were maximal, rHuTNF alpha produced no further stimulation. These data suggest that the secretory activities of synovial fibroblasts can be influenced by a combination of cytokines and is dependent on the type of cytokine present and its concentration.
Meyer
F A
FA
Department of Rheumatology, Ichilov Hospital, Tel-Aviv, Israel.
Yaron
I
I
Yaron
M
M
D002478:Cells, Cultured; D004336:Drug Antagonism; D004338:Drug Combinations; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D003012:Microbial Collagenase / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004338:Drug Combinations; D007375:Interleukin-1; D011458:Prostaglandins E; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006820:Hyaluronic Acid; D003012:Microbial Collagenase