IN-VITRO MODULATION OF CYTOKINE, CYTOKINE INHIBITOR, AND PROSTAGLANDIN-E RELEASE FROM BLOOD MONONUCLEAR-CELLS AND SYNOVIAL FIBROBLASTS BY ANTIRHEUMATIC DRUGS

Objective, To assess the effect of various antirheumatic drugs on cyto kine, cytokine inhibitor, and prostaglandin E (PGE) production by norm al blood mononuclear cells (MNC) and rheumatoid arthritis (RA) synovia l fibroblasts in vitro. Methods, MNC from healthy donors and RA synovi al fibroblasts were preincubated with or without prostaglandin E-2 (PG E(2)), indomethacin, dexamethasone, gold sodium thiomalate (GSTM), met hotrexate (MTX), and cyclosporin A (CyA), and then cultured in the abs ence or presence of interleukin-1 beta (IL-1 beta) or tumor necrosis f actor-alpha (TNF-alpha) for 48 h. We characterized cytokines such as I L-1 beta, IL-X, monocyte chemoattractant protein-1 (MCP-1), and cytoki ne inhibitors such as IL-1 receptor antagonist (IL-1ra) and soluble TN F receptors (sTNFR p55 + p75) as well as PGE in the cell-free culture supernatants. Results, In MNC and synovial fibroblast cultures dexamet hasone, GSTM, and PGE(2) most markedly downregulated spontaneous and/o r cytokine stimulated production of IL-1 beta, IL-1ra, IL-8, and MCP-1 , whereas sTNFR shedding was not affected. In contrast, MTX and CyA ha d only marginal or no effects on mediator release, whereas indomethaci n inhibited only PGE production. Conclusion. Among several antirheumat ic drugs examined, dexamethasone and GSTM exhibited the most potent in hibitory effects on inflammatory cytokine and cytokine inhibitor produ ction by blood mononuclear cells and synovial fibroblasts. These drugs may exert their antiinflammatory actions by unspecific suppression of monocyte and fibroblast secretory function.