Endogenously Produced Interleukin 6 is an Accessory Cytokine for Dendritic Cell Hematopoiesis

The aim of this study was to investigate the role of interleukin 6 (IL‐6) in normal dendritic cell (DC) hematopoiesis. We used an enzyme‐linked immunosorbent assay to quantitate IL‐6 levels in CD34 + progenitor cell cultures favoring monocyte (mono) development versus those supporting mono‐DC growth, and studied the neutralizing effects of αIL‐6 antibody on DC hematopoiesis. IL‐6 levels in mono cultures (GM‐CSF alone) were detected by day 4 and remained constant (∼100 pg/ml) for 18 days. In mono‐DC cultures, higher IL‐6 levels correlated with DC content and development. Short‐term mono‐DC cultures initiated with GM‐CSF + tumor necrosis factor (TNF) + stem cell factor (SCF) exhibited increases in IL‐6 levels until day 11 (peak DC growth). By day 18, the levels had declined and cells expressing typical DC features were no longer present. Long‐term mono‐DC cultures sustained with GM‐CSF + TNF + SCF contained the highest IL‐6 levels (671 pg/ml) on day 11. In these cultures, DCs and higher IL‐6 levels persisted beyond 18 days. Anti‐IL‐6 profoundly inhibited cell proliferation associated with DC hematopoiesis when added on days 0, 2 and 5 to GM‐CSF + TNF + SCF cultures, indicating that various stages of mono‐DC development rely on IL‐6. There was no reduction in the T cell response when αIL‐6 was added to mixed leukocyte reaction cultures containing mature DCs as stimulators. Thus, αIL‐6 appears to downregulate developmental processes associated with optimal mono‐DC growth, but not the effector functions of mature DCs. These studies substantiate the importance of IL‐6 as a secondary cytokine during DC development and provide insight into another control point in the DC pathway.