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

Abstract

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.