Cytokine regulation of colony-stimulating factor (CSF) production in cultured human synovial fibroblasts. II. Similarities and differences in the control of interleukin-1 induction of granulocyte-macrophage CSF and granulocyte-CSF production

Abstract

Synovial fibroblasts are likely to be a significant source of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF), which could be crucial to the pathogenesis of rheumatoid arthritis. Using specific enzyme-linked immunosorbent assays (ELISAs) and Northern analysis, GM-CSF and G-CSF expression were followed in human synovial fibroblast-like cells in response to a number of agents, either alone or in the presence of an optimal stimulatory concentration of interleukin-1 (IL-1). For both CSFs, interferon-gamma (100 U/mL) did not increase their levels but dramatically suppressed the stimulatory action of IL-1, while basic fibroblast growth factor (10(-8) mol/L), although nonstimulatory by itself, potentiated IL-1 action. The glucocorticoid, dexamethasone (10(- 7) mol/L), inhibited IL-1-stimulated CSF production. However, evidence was obtained for noncoordinated CSF regulation. Cyclooxygenase inhibitors potentiated the action of IL-1 on GM-CSF synthesis but suppressed G-CSF synthesis, suggesting that endogenous cyclooxygenase products can have opposite effects in modulating the levels of each CSF. Also, the lymphokine, IL-4 (250 pmol/L), slightly inhibited GM-CSF formation in the presence of IL-1 but elevated the G-CSF levels in these cultures without having an effect by itself. Transforming growth factor beta (less than or equal to 20 ng/mL) did not modulate levels of either CSF. Mesenchymal cell production of both GM-CSF and G-CSF is generally viewed as being under coordinate control; our findings suggest that their synthesis in IL-1-stimulated human synoviocytes can be modulated by a number of agents, in some cases with divergent actions depending on which CSF is examined.

Modulation of Proinflammatory Responses to Pneumocystis carinii f. sp. muris in Neonatal Mice by Granulocyte-Macrophage Colony-Stimulating Factor and IL-4: Role of APCs

“…Bronchial epithelial cells are the major sources of GM-CSF (34), and these cells are not fully matured in the neonatal lungs (35). Furthermore, high levels of glucocorticoids in the neonatal lungs (35) required for postnatal development and maturation may have inhibitory effects on GM-CSF induction (36,37). The lack of GM-CSF also influenced TNF-␣, IL-12, and IL-18 expression in the neonatal lungs because exogenous GM-CSF administration resulted in up-regulated expression of these cytokines (Fig.…”

Synovial tissue macrophages: friend or foe?

“…This suggests that, at least in the mouse, tissue-resident and monocyte-derived macrophages may respond differently to ‘on demand’ signals. In RA synovium, the phenotype of monocyte-derived macrophages is shaped by the interaction with synovial fibroblasts that are epigenetically reprogrammed to produce a wide range of mediators,81 for example, GM-CSF that potentiates the proinflammatory activation of macrophages 82 83. In addition, danger-associated molecular pattern molecules (DAMPs) released in the damage joint, for example, tenascin-C, bind to TLR4 and trigger proinflammatory cytokine production by macrophages 84.…”

Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis

“…Synovial fibroblasts have been identified as a significant source of GM-CSF. 31 We assessed their contribution by stimulating cultured synovial fibroblasts with IL-1β and TNFα, two cytokines produced by synovial macrophages and thought to be responsible for the activated phenotype of RA synovial fibroblasts. 32 Whereas levels of GM-CSF were undetectable following stimulation with up to 50 ng/mL TNFα (data not shown), IL-1β was an effective stimulus for GM-CSF production ( figure 1 B).…”