TY - JOUR
T1 - NF-κB p50 regulates C/EBPα expression and inflammatory cytokine-induced neutrophil production
AU - Wang, Dehua
AU - Paz-Priel, Ido
AU - Friedman, Alan D.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - NF-κB 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/EBPαis required for the development of monocytic and granulocytic myeloid cells from early progenitors, and NF-κB and C/EBPβ cooperatively induce several inflammatory mediators. Having found that C/EBPα binds NF-κB p50 preferentially compared with NF-κB p65, we have now investigated myelopoiesis in nfkb1(-/-) mice lacking NF-κB 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-κB p50, we assessed the expression of several myeloid regulatory proteins in lineage-negative, immature myeloid cells. Although PU.1, C/EBPα, and STAT3 levels were unchanged, C/EBPα protein and RNA levels were reduced ∼3-fold in the absence of NF-κB p50. In addition, NF-κB p50 and C/EBPα bound the endogenous C/EBPα promoter in a chromatin immuno-precipitation assay, and NF-κB p50 trans activated the C/EBPα promoter, alone or in cooperation with C/EBPα. Despite reduction of C/EBPα, 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-κB p50 induction of C/EBPα transcription.
AB - NF-κB 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/EBPαis required for the development of monocytic and granulocytic myeloid cells from early progenitors, and NF-κB and C/EBPβ cooperatively induce several inflammatory mediators. Having found that C/EBPα binds NF-κB p50 preferentially compared with NF-κB p65, we have now investigated myelopoiesis in nfkb1(-/-) mice lacking NF-κB 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-κB p50, we assessed the expression of several myeloid regulatory proteins in lineage-negative, immature myeloid cells. Although PU.1, C/EBPα, and STAT3 levels were unchanged, C/EBPα protein and RNA levels were reduced ∼3-fold in the absence of NF-κB p50. In addition, NF-κB p50 and C/EBPα bound the endogenous C/EBPα promoter in a chromatin immuno-precipitation assay, and NF-κB p50 trans activated the C/EBPα promoter, alone or in cooperation with C/EBPα. Despite reduction of C/EBPα, 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-κB p50 induction of C/EBPα transcription.
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U2 - 10.4049/jimmunol.0803861
DO - 10.4049/jimmunol.0803861
M3 - Article
C2 - 19380823
AN - SCOPUS:66949165544
SN - 0022-1767
VL - 182
SP - 5757
EP - 5762
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -