PRODUCTION OF MACROPHAGE-COLONY-STIMULATING FACTOR (M-CSF) BY HUMAN ARTICULAR-CARTILAGE AND CHONDROCYTES - MODULATION BY INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA

A specific radioimmunoassay was employed to demonstrate that human art icular cartilage and chondrocyte monolayers in organ and cell culture, respectively, produce macrophage colony-stimulating factor (M-CSF) in response to stimulation with interleukin-1alpha (IL-1alpha), IL-1beta , tumor necrosis factor alpha (TNFalpha) and TNFbeta. Optimum doses we re 10-100 U/ml for IL-1 (0.06-0.6 nM IL-1alpha; 0.02-0.2 nM IL-1beta) and 1-10 nM for TNFalpha. Low levels of M-CSF were observed in the sup ernatants of nonstimulated cultures while increased levels of M-CSF in response to IL-1alpha and TNFalpha were detected following 2 h exposu re to the cytokines. IL-1alpha and TNFalpha did not show synergy for t he production of M-CSF when both cytokines were added to cultures. Act inomycin D and cycloheximide inhibited both the basal and IL-1alpha-in duced production of M-CSF, suggesting a requirement for de novo RNA an d protein synthesis. Cytokine-induced M-CSF production was also inhibi ted by the antiinflammatory corticosteroid, dexamethasone, but not by the cyclooxygenase inhibitor, indomethacin. The cytokines IL-4, IL-6, platelet-derived growth factor, leukemia inhibitory factor, transformi ng growth factor-beta and interferons -alpha and -gamma, each had litt le or no effect on M-CSF levels, while basic fibroblast growth factor, lipopolysaccharide, and retinoic acid were each weak stimuli. We prop ose that chondrocyte M-CSF production in response to IL-1 and TNFalpha , and the concurrent destruction of cartilage by these cytokines, coul d provide a mechanism for the chronic nature of rheumatoid disease.