Cw. Castor et al., CONNECTIVE-TISSUE ACTIVATION .37. EFFECTS OF CYTOKINE COMBINATIONS, IMPLICATIONS FOR AN INTEGRATED CYTOKINE NETWORK, Journal of rheumatology, 24(11), 1997, pp. 2080-2089
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.