B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1-dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells.

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor important for the differentiation and function of several types of immune cells. Because skin serves as a physical barrier and acts as an immune sentinel, we investigated whether Blimp-1 is involved in epidermal immune function. We show that Blimp-1 expression is reduced in skin lesions of some human eczema samples and in stimulated primary keratinocytes. Epidermal-specific deletion of PR domain containing 1, with ZNF domain ( Prdm1 ), the gene encoding Blimp-1, in adult mice caused spontaneously inflamed skin characterized by massive dermal infiltration of neutrophils/macrophages and development of chronic inflammation associated with higher levels of cytokines/chemokines, including granulocyte colony-stimulating factor (G-CSF), and enhanced myelopoiesis in bone marrow. Deletion of Prdm1 in the epidermis of adult mice also led to stronger inflammatory reactions in a tape-stripping test and in a disease model of contact dermatitis. The elevated G-CSF produced by keratinocytes after deletion of Prdm1 in vitro was mediated by the transcriptional activation of FBJ osteosarcoma oncogene ( Fos ) and fos-like antigen 1 ( Fosl1 ). Systemic increases in G-CSF contributed to the inflammatory responses, because deletion of the G-CSF gene [colony stimulating factor 3, ( Csf3 )] prevented neutrophilia and partially ameliorated the inflamed skin in Prdm1- deficient mice. Our findings indicate a previously unreported function for Blimp-1 in restraining steady-state epidermal barrier immunity.

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Transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) is a master regulator of plasma cell differentiation. Here we show that Blimp-1 is covalently modified by SUMO1 at lysine 816, a modification mediated by SUMO E3 ligase PIAS1. Mutation of Blimp-1 lysine 816 reduces transcriptional repression--correlating with a reduced interaction with a histone deacetylase, HDAC2--and impairs differentiation of antibody-secreting cells. Thus, the SUMO pathway critically regulates Blimp-1 function during plasma cell differentiation.