STIMULATION OF HUMAN SYNOVIAL CELL-DNA SYNTHESIS BY IRON

Objective. To determine the effect of iron and cytokines on proliferat ion of synovial cells (SC), we isolated SC obtained at the time of tot al knee replacement from 11 patients with rheumatoid arthritis (RA) an d 2 with osteoarthritis (OA) following enzymatic treatment of synovial tissue. Methods. SC were cultured in the presence of ferric citrate o r sodium citrate at concentrations of 0, 0.01, 0.1, and 1 mM for 72 h. In vitro synthesis of DNA by SC was measured by intracellular H-3-thy midine uptake. Results. Synthesis of DNA by SC was significantly enhan ced by ferric citrate but not sodium citrate. The maximum synthesis wa s observed following stimulation with 0.1 mM ferric citrate and was ob tained after 3 days of culture, thereafter declining until Day 7. This stimulatory effect of ferric citrate was observed in all specimens of SC tested. In our examination of the concomitant addition of each of 8 different recombinant human cytokines with 0.1 mM ferric citrate on SC DNA synthesis, 4 of them, i.e., interleukin-1 beta (IL-1 beta), IL- 7, tumor necrosis factor or (TNF alpha) and interferon gamma (IFN-gamm a) each enhanced the synthesis of SC DNA at concentrations ranging fro m 1 to 100 u/ml, while IL-1 beta, IL-7, TNF alpha or IFN-gamma togethe r showed an additive effect. No significant effect was shown by IL-2, IL-6, IL-8, or granulocyte colony stimulating factor (G-CSF). Conclusi on. Iron stimulated in vitro SC DNA synthesis and had an additive effe ct on the activity of human cytokines for SC proliferation. Iron may p lay a role in the proliferation of synovial cells in patients with RA synovitis.