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

Abstract

The effects of binary combinations of the recombinant human cytokines, interleukin-lp (rHuIL-lP), tumor necrosis factor a (rHuTNFa), and y-interferon (rHuyIFN) 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-l/? and rHuTNFa alone, but not by rHuy-IFN. Stimulation with rHuIL-lP and rHuTNFa occurred at femtomolar and picomolar concentrations, respectively, and maximal stimulation by rHuIL-lP was several times greater than that by rHuTNFa. Stimulation of PGE and collagenase production with rHuIL-lp or rHuTNFa was depressed by rHuyIFN, depending on the concentration used. In contrast, stimulation of HA production with rHuIL-lP or rHuTNFa was unaffected or increased somewhat with rHuy-IFN. Combinations of rHuIL-lP and rHuTNFa had marked synergistic effects on PGE and collagenase production. However, when rHuIL-1P effects were maximal, rHuTNFa had an additive effect. These cytokines had only additive effects on HA produc-

Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down‐regulation by tumor necrosis factor α blockade in spondylarthropathy

“…In the synovial compartment, they are produced by macrophages, synovial fibroblasts, endothelial cells, neutrophils, and chondrocytes (14). Active up-regulation of MMPs is observed after stimulation with proinflammatory cytokines such as IL-1␤ (15) and TNF␣ (15)(16)(17)(18). Their biologic relevance has been linked to joint destruction (19,20), angiogenesis (21), and cell trafficking (22).…”

Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures

“…Increased synthesis of HA by connective tissue cells is an integral part of connective tissue activation, as described by Sisson et al (29). There is a close correlation between stimulation of HA production and that of PGE 2 , which are both induced by IL-1␤ and TNF␣ (30). We found elevated levels of HA in the sera of women with fibromyalgia (31), and others have reported elevated levels in patients with RA and OA, correlating with disease activity and disease progression (32,33).…”

“…Synergistic and additive effects of these 2 cytokines ( Figure 9) were previously described (30). IL-1␣ and IL-1␤ showed very similar effects in our model (16).…”

Modulation by proinflammatory cytokines of Fas/Fas ligand-mediated apoptotic cell death of synovial cells in patients with rheumatoid arthritis (RA)

“…It is well known that TNF-a and IL-1b elicit a concentrationdependent increase in 3 H-thymidine incorporation of synovial cells in patients with RA [7,8,10]. It is thus possible that proinflammatory cytokines may inhibit apoptotic cell death of RA synovial cells.…”

“…This histological picture may be associated with an imbalance between cell proliferation and cell death. It is evident that excessive production of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-a) and IL-1b in the joints leads to the enhanced proliferation of RA synovial cells, resulting in the formation of pannus that causes damage of articular cartilage [6][7][8][9][10]. However, little is known about how synovial cell death is controlled in the joints in patients with RA.…”