Synergistic, additive, and antagonistic effects of interleukin‐1β, tumor necrosis factor α, and γ‐interferon on prostaglandin e, hyaluronic acid, and collagenase production by cultured synovial fibroblasts

The effects of binary combinations of the recombinant human cytokines, interleukin‐1β (rHuIL‐1β), tumor necrosis factor α (rHuTNFα), and γ‐interferon (rHuγ‐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‐1β and rHuTNFα alone, but not by rHuγ‐IFN. Stimulation with rHuIL‐1β and rHuTNFα occurred at femtomolar and picomolar concentrations, respectively, and maximal stimulation by rHuIL‐1β was several times greater than that by rHuTNFã. Stimulation of PGE and collagenase production with rHuIL‐1β or rHuTNFα was depressed by rHuγ‐IFN, depending on the concentration used. In contrast, stimulation of HA production with rHuIL‐1β or rHuTNFα was unaffected or increased somewhat with rHuγ‐IFN. Combinations of rHuIL‐1β and rHuTNFα had marked synergistic effects on PGE and collagenase production. However, when rHuIL‐1β effects were maximal, rHuTNFα had an additive effect. These cytokines had only additive effects on HA production, however, and when rHuIL‐1β effects were maximal, rHuTNFα 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.