Various cytokines,
chemokines and transcription factors are involved in mononuclear phagocyte development and differentiation, and GM-CSF and Flt3L are key cytokines among them.[4, 6, 9, 35] Over-expression of GM-CSF in transgenic animals or mice receiving daily injections of a modified form of recombinant GM-CSF resulted in a significant expansion in DCs in the spleen and thymus, with the expanded DC populations most likely representing inflammatory DCs.[36, 37] The mice had a massive expansion of pDCs and cDCs in the spleen after injection of the recombinant Flt3L cytokine.[37, 38] Type I interfeorn-induced mice exhibited increased populations of pDCs and suppressed cDCs. On the other hand, many transcription factors have been reported in regulating development buy BYL719 of monocytes, macrophages and DCs. Transcription factors including the interferon regulatory factor family (IRF8, IRF4 and IRF1); STAT3, STAT5 and STAT1; E2-2, Id2 and Spi-B regulate mononuclear phagocyte development.[4, 35] To investigate the molecular mechanisms of the effect of Fli-1 on mononuclear phagocyte development, we cultured MPPs from BM cells from both Fli-1∆CTA/∆CTA B6 mice and wild-type B6 mice, and examined differences among key genes that impact mononuclear phagocyte development. We found
that expression of Flt3L was significantly increased in MPPs from Fli-1∆CTA/∆CTA B6 mice compared with wild-type littermates (Fig. 5). Furthermore, we demonstrated that the Fli-1 protein binds directly to the promoter FDA-approved Drug Library screening region of the Flt3L gene (Fig. 6). We are actively investigating how Fli-1 regulates the expression of the Flt3L gene. A previous report demonstrated that STAT3 can be activated by Flt3L signalling, and that STAT3 regulates the differentiation of pDCs and cDCs from progenitors.[39] We found that expression of STAT3 was higher in MPPs from Fli-1∆CTA/∆CTA B6 mice compared with wild-type mice although the difference was not statistically significant. In summary, we have found that Fli-1∆CTA/∆CTA B6 mice had significantly increased populations of HSCs and CDPs in BM, increased pre-cDCs, cDCs, pDCs
and macrophages in the spleen, and increased pre-cDCs and monocytes in PBMCs compared MG-132 clinical trial with wild-type littermates. Expression of Flt3L in MPPs from Fli-1∆CTA∆CTA BM cells was significantly increased when compared with wild-type B6 mice and Fli-1 binds the promoter region of Flt3L. The CTA domain of Fli-1 negatively regulates mononuclear phagocyte development and Fli-1 is one of the transcriptional factors regulating the HSC and myeloid cell development in mice. This study was supported in part by National Institutes of Health grants (AR056670 to X.K.Z.) and the Medical Research Service, Department of Veterans Affairs (to G.G. and X.K. Z.). We thank Dr Mara Lennard-Richard at the Medical University of South Carolina for critical reading of the manuscript.