We recently demonstrated that IgG from patients with systemic lupus erythematosus (SLE) in combination with U937 cells made apoptotic by UV-irradiation, can induce interferon-α (IFN-α) production in normal peripheral blood mononuclear cells (PBMC). In the present study we show by flow cytometry that the actual IFN-α producing cells (IPC) among PBMC had the same phenotype (HLA-DR+, CD4+, CD11b−, CD11c−, CD14−, CD19−, CD32−, CD36+, CD40+, CD45RA+, CD68+, CD83+, CD86−, IL-3R+ and IL-10R−) and low frequency (approximately 2/10⁴PBMC) as the IPC activated by Herpes simplex virus type I. Consequently, these cells correspond to the natural IPC, also described as type 2 precursor dendritic cells. We also demonstrated that cytokines of possible importance in the pathogenesis in SLE had effects on the IFN-α production. Specifically, the IFN-α production was strongly increased by the type I IFNs, IFN-α and -β, but markedly inhibited by IL-10 and also to some extent by TFN-α. In contrast, the cytokines IFN-γ, IL-6, TGF-β and GM-CSF had no clear effects. No production of IL-10 was detected in PBMC stimulated by apoptotic U937 cells and SLE IgG. These results may explain the cause of the ongoing IFN-α production in SLE patients and its relation to the autoimmune process.