OBJECTIVE: Interferon-alpha (IFNalpha)-producing plasmacytoid dendritic cells (PDCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). IFNalpha-related genes are highlighted among SLE susceptibility alleles and are characteristically expressed in the blood of patients with SLE, while in mouse models of lupus, PDC numbers and IFNalpha production are increased. This study was undertaken to investigate the effects of inhibitors that selectively target different antiapoptotic molecules on the survival of PDCs. METHODS: PDC numbers, in vitro survival, and expression of antiapoptotic molecules were evaluated in lupus-prone (NZB x NZW)F1 (NZB/NZW) mice. The impact of Bcl-2 antagonists and glucocorticoids on PDCs was evaluated in vitro and in vivo. IFNalpha production by NZB/NZW mice was evaluated before and after treatment with Bcl-2 antagonists. RESULTS: PDCs, but not lymphoid tissue-resident conventional DCs, largely relied on the antiapoptotic protein Bcl-2 for survival. The enlarged PDC compartment in NZB/NZW mice was associated with selectively prolonged survival and increased Bcl-2 transcription. Functionally, this resulted in enhanced production of IFNalpha. Bcl-2 inhibitors selectively killed mouse and human PDCs, including PDCs from SLE patients, but not conventional DCs, dampened IFNalpha production by PDCs, and synergized with glucocorticoids to kill activated PDCs. CONCLUSION: Enhanced PDC survival is a likely contributing factor to enhanced IFNalpha production by lupus PDCs. Bcl-2 antagonists potently and selectively kill PDCs and reduce IFNalpha production. Thus, we believe that they are attractive candidates for treating PDC-associated diseases.