CONNECTIVE-TISSUE ACTIVATION .37. EFFECTS OF CYTOKINE COMBINATIONS, IMPLICATIONS FOR AN INTEGRATED CYTOKINE NETWORK

Objective. Since many cytokines have been identified in chronically in flamed human synovium, it is possible that particular cytokines or com binations of cytokines play dominant roles in driving or inhibiting me tabolic processes important to inflammation, To assess these possibili ties, we compared selected effects of individual cytokines and their b inary, ternary, and higher combinations in human synovial cell culture s. Methods. Cytokines studied known to occur in human synovial tissue included: interleukin 1 beta (IL-1 beta), IL-6, tumor necrosis factor- alpha, granulocyte macrophage colony stimulating factor, interferon-ga mma, acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platele t derived growth factor, transforming growth factor-beta 1, connecting tissue activating peptide-IU[, and epidermal growth factor, The growt h related effects of these agents singly and in combinations were asse ssed by measuring newly synthesized [H-3]DNA and [C-14]GAG (glycosamin oglycan) in human synovial cell cultures. Cytokine induced synthesis o f prostaglandin E-2 (PGE(2)) was measured by ELISA. Results. Most cyto kine combinations resulted in additive/synergistic anabolic effects, e xcept when IL-1 beta was present; IL-1 beta was markedly antagonistic to the mitogenic effects Of other cytokines tested. Combinations of pl atelet derived cytokines were the most potent stimulators of DNA synth esis, while combinations of synovial derived cytokines were more activ e in stimulating GAG synthesis. Synovial cells exposed simultaneously to both platelet and synovial derived cytokines produced large quantit ies of [C-14]GAG and showed a modest increase in [H-3]DNA synthesis. I L-1 beta, alone or in combinations, was dominant with respect to stimu lation of PGE(2) synthesis. Acetylsalicylic acid substantially interfe red with all the effects of cytokine combinations measured. Conclusion , Quantitative alterations in synovial cell synthesis of GAG and DNA v aried greatly depending on the ambient mixture of cytokines. Virtually all combinations of cytokines tested gave rise to large increases in synovial cell synthesis of GAG. Four platelet derived cytokines, a ''p hysiologic combination,'' appeared to be dominant agents in stimulatin g DNA synthesis. This effect was profoundly reduced by the antagonisti c effect of IL-1 beta, mediated in part by PGE(2). The patterns of cyt okine combination induced metabolic effects suggest that the ''cytokin e network'' has a significant measure of redundancy with respect to co ntrol of synovial cell metabolism.