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

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Abstract
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.

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