IL-6 is a regulator of inflammatory and immunological processes and high levels of this cytokine have recently been shown to be present in synovial fluids from inflammatory and degenerative arthropathies. Synovial fluid IL-6 may in part be a product of synoviocytes that have previously been identified as a source of IL-6. To further define intraarticular sources of IL-6, we examined the ability of chondrocytes to produce IL-6 and studied its modulation by inflammatory cytokines and homeostatic regulators of chondrocyte function. Human articular chondrocytes isolated from normal and osteoarthritic joints released low levels of IL-6 when cultured in the presence of serum. The inflammatory cytokines IL-1, and, to a lesser extent, TNF-alpha and IFN-gamma increased IL-6 production. Among the growth factors known to act on chondrocytes, only transforming growth factor-beta, but not epidermal growth factor. fibroblast growth factor, insulin growth factor-1 and 2, platelet growth factor or insulin, was able to significantly increase IL-6 synthesis. Analysis of hormonal influences on chondrocyte IL-6 production showed that testosterone and estradiol synergized with IL-1 in the induction of IL-6. Hydrocortisone, at 10 ng/ml, reduced IL-1-induced IL-6 production by more than 50%. Chondrocyte-derived IL-6 stimulated acute phase protein synthesis and hybridoma cell proliferation. These biological activities were neutralized by a specific antibody to IL-6. Metabolic labeling and immunoprecipitation studies showed that IL-1 induced de novo synthesis of IL-6 and that the IL-6 proteins secreted by chondrocytes were similar to those from fibroblasts. These results demonstrate that chondrocytes are able to produce IL-6 in response to physiologic and inflammatory stimuli. Chondrocytes probably contribute to the increased synovial fluid levels of IL-6 in inflammatory and degenerative conditions of cartilage, and IL-6 may serve as a mediator to coordinate responses to cartilage injury.