The MDP give rise to monocytes and common DC progenitors (CDPs). Although monocytes can directly participate in immune responses or differentiate into macrophages or DCs, the differentiation potential of CDPs is restricted to the DC lineage. Common DPs give rise to cDCs and pre-classical DCs (pre-cDCs), which subsequently give rise to DCs. In these differentiation steps, several cytokines and transcription factors have been identified as key molecules in regulating mononuclear
phagocyte development. Several reports have demonstrated that granulocyte–macrophage colony-stimulating factor (GM-CSF) drives inflammatory DC development from monocytes, and FMS-like tyrosine kinase 3 ligand (Flt3L) plays a critical
role in the development of cDCs and pDCs in the AZD1208 steady state.[4, 5, 9] The use of knockout mouse models revealed key roles of several transcription factors in DC development. Many transcription factors – including interferon regulatory factors, signal transducers and activators of transcription proteins (STATs), and Ets gene family members (SpiB, PU.1) –participate in DC differentiation and homeostasis.[4, 5, 9-11] The Fli-1 gene is a member of the Ets gene family of transcription factors.[12, 13] Members of the Ets gene family are found in genomes of diverse organisms, including Drosophila, Xenopus, sea urchin, chicken, mouse and human.[14-16] Like selleck chemicals other Ets gene family members, Fli-1 has the conserved DNA binding sequence, the Ets domain. Ets proteins bind to DNA sequences that contain a consensus GGA(A/T) core motif (Ets binding site) and function as either transcriptional activators or repressors.[15, 16] It has also been demonstrated that the 17-DMAG (Alvespimycin) HCl Fli-1 transcription factor plays an important role in megakaryocytic
differentiation and B-cell development.[17-22] Targeted disruption of the Fli-1 gene resulted in haemorrhage into the neural tube and embryonic death, due in part to thrombocytopenia. We have reported that the number of platelets in the peripheral blood was reduced, and platelet aggregation and activation were also impaired in homozygous mutant Fli-1 mice that express Fli-1 protein (Fli-1∆CTA) with a truncated C-terminal regulatory (CTA) domain. Expression of Fli-1 has been implicated in systemic lupus erythematosus in both human patients and murine models.[25-27] In this report, we investigated the role of Fli-1 in development of monocytes, macrophages and DCs. We found that populations of monocytes, macrophages and DCs were significantly increased in Fli-1∆CTA/∆CTA mice compared with wild-type littermates, and expression of Fli-1 in both haematopoietic cells and stromal cells has an effect on mononuclear phagocyte development. Expression of Flt3L was statistically higher in multipotent progenitors from Fli-1∆CTA/∆CTA mice compared with wild-type controls, and Fli-1 directly binds to the promoter of the Flt3L gene.