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B p50 Regulates C/EBP
Expression and Inflammatory Cytokine-Induced Neutrophil Production1Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD 21231
NF-
B is a key transcriptional inducer of the inflammatory response in mature myeloid cells, and also stimulates cell survival, but its role in immature myeloid cell development has not been well characterized. C/EBP
is required for the development of monocytic and granulocytic myeloid cells from early progenitors, and NF-B and C/EBPβ cooperatively induce several inflammatory mediators. Having found that C/EBP binds NF-B p50 preferentially compared with NF-B p65, we have now investigated myelopoiesis in nfkb1(–/–) mice lacking NF-B p50. Absence of p50 leads to a significant reduction in the number of granulocytic progenitors, CFU-granulocyte, obtained with G-CSF or GM-CSF in vitro and reduces neutrophil production in vivo in response to G-CSF, with preservation of monopoiesis in vitro in response to cytokines or LPS. To gain insight into the mechanism underlying reduced granulopoiesis in the absence of NF-B p50, we assessed the expression of several myeloid regulatory proteins in lineage-negative, immature myeloid cells. Although PU.1, C/EBPβ, and STAT3 levels were unchanged, C/EBP protein and RNA levels were reduced 
3-fold in the absence of NF-B p50. In addition, NF-B p50 and C/EBP bound the endogenous C/EBP promoter in a chromatin immunoprecipitation assay, and NF-B p50 trans activated the C/EBP promoter, alone or in cooperation with C/EBP. Despite reduction of C/EBP, G-CSFR and M-CSFR levels were maintained in total marrow and in lineage-negative cells. Together, these data indicate that acute inflammation not only activates mature myeloid cells, but also stimulates neutrophil production via NF-B p50 induction of C/EBP transcription.
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1 This work was supported by National Institutes of Health Grant HL082948, a grant from the Children’s Cancer Foundation (to A.D.F.), and grants from the St. Baldrick’s Foundation and Alex’s Lemonade Stand Foundation (to I.P.-P.).
2 D.W. and I.P.-P. contributed equally and share first authorship.
3 Address correspondence and reprint requests to Dr. Alan D. Friedman, Johns Hopkins University, CRB I Room 253, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: afriedm2{at}jhmi.edu
4 Abbreviations used in this paper: BR, basic region; ANC, absolute neutrophil count; CFU-G, CFU-granulocyte; CFU-GM, CFU-granulocyte-monocyte; CFU-M, CFU-monocyte; ChIP, chromatin immunoprecipitation; CLP, common lymphoid progenitor; FL, Flt3 ligand; HI-FBS, heat-inactivated FBS; HSC, hematopoietic stem cell; MEP, megakaryocyte-erythroid progenitor; SCF, stem cell factor.
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