ENDOGENOUS PRODUCTION OF TUMOR-NECROSIS-FACTOR BY PRIMARY CULTURES OFMURINE CALVARIAL CELLS - INFLUENCE ON IL-6 PRODUCTION AND OSTEOCLAST DEVELOPMENT

We have previously shown that tumor necrosis factor (TNF) and interleu kin-1 (IL-1) acted synergistically to stimulate the production of IL-6 by bone marrow stromal and osteoblastic cells; and that an antibody t o IL-6 inhibited TNF-induced osteoclast development in murine calvaria l cell cultures. Prompted by this evidence, we have now examined wheth er TNF and/or IL-1 are produced by murine calvarial cells, and whether these cytokines are involved in IL-6 production and osteoclast format ion. When cultured under basal conditions, calvarial cells produced TN F and IL-6, and were able to form bone resorbing osteoclasts. A neutra lizing antibody against TNF suppressed both basal IL-6 production and the formation of bone resorbing osteoclasts. The anti-TNF antibody als o inhibited IL-6 production in response to exogenous IL-1 or parathyro id hormone (PTH). In contrast, a neutralizing anti-IL-1 receptor antib ody had no effect on basal, TNF- or PTH-stimulated IL-6 production. Th ese findings suggest that TNF, but not IL-1, is produced by murine bon e cells and that endogenous TNF induces the IL-6 production, osteoclas t formation, and bone resorption exhibited by these cultures under bas al conditions. Furthermore, bone cell-derived TNF amplifies the stimul atory effect of exogenous IL-1 or PTH on IL-6 production by calvarial cells.