Objective. Interferon-␣ (IFN␣) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFN␣ production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.Methods. Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFN␣ production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E 2 (PGE 2 ), reactive oxygen species (ROS), or the cytokines IFN␣2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor ␣ (TNF␣) were explored.Results. Monocytes inhibited IFN␣ production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFN␣ production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFN␣2b/GM-CSF increased their IFN␣ production. RNA-containing ICs caused production of ROS, PGE 2 , and TNF␣, especially in monocytes. These mediators and IL-10 suppressed IFN␣ production in PBMC cultures, with ROS and PGE 2 also inhibiting IFN␣ production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFN␣2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.Conclusion. IFN␣ production induced by RNAcontaining ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro-and antiinflammatory molecules. This should be considered when designing and applying new therapies.