Activation by CpG Oligodeoxynucleotides Protects Bone Marrow-Derived Dendritic Cells from Apoptosis: A Transcriptomic and Bioinformatic Study

ABSTRACT

Despite the essential role of dendritic cells in the priming of immune responses, the cellular and molecular mechanisms involved in regulating apoptosis and survival of dendritic cells are still poorly documented. Experimental data has suggested that activation of dendritic cells through either T cells or by engagement of pathogen-associated molecular patterns recognition suppresses dendritic cell apoptosis and promotes survival. In this study we investigated the mechanisms involved in regulating bone marrow derived dendritic cells (BMDCs) survival and apoptosis after cytidinephosphate- guanosine oligodeoxynucleotide (CpG-ODN) treatment. We found that addition CpG-ODN to BMDC cultures protected cells from spontaneous apoptosis; in addition, CpG-ODN also protected BMDCs from camptothecin-induced apoptosis. To identify transcription factors controlling CpG-ODN-mediated BMDCs survival we employed DNA microarrays, gene clustering and transcription element listening system (TELiS), a sequence-based bioinformatic tool that identifies transcription factor binding motifs that are over-represented among the promoters of up- or down-regulated genes. Our analysis revealed that several transcription factors may play key roles in regulating CpG-ODN-induced BMDCs survival. Interestingly, the CCAAT/enhancer binding protein alpha (C/EBPα.) was significantly over-represented among the promoters of the up-regulated genes; however its expression levels in nuclear extracts was significantly reduced following CpG-ODN treatment, suggesting that CpG-ODN-mediated survival of BMDCs is associated with decreased activation of C/EBPα. In conclusion, our study suggested that in addition to NF-κB and AP-1, other transcription factors, such as C/EBPα, also contribute to the regulation of CpG-ODN induced BMDC survival.