Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.1107751 on February 13, 2008

Published online before print February 13, 2008
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(Journal of Leukocyte Biology. 2008;83:1277-1285.)
© 2008 by Society for Leukocyte Biology

LRG-accelerated differentiation defines unique G-CSFR signaling pathways downstream of PU.1 and C/EBP{epsilon} that modulate neutrophil activation

Jing Ai*, Lawrence J. Druhan{dagger}, Melissa G. Hunter{ddagger}, Megan J. Loveland* and Belinda R. Avalos*,1

* Davis Heart and Lung Research Institute and Division of Hematology/Oncology,
{dagger} Division of Cardiovascular Medicine, Department of Internal Medicine, and
{ddagger} Division of Pulmonary and Critical Care Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA

1Correspondence: Davis Heart and Lung Research Institute and Division of Hematology/Oncology, The Ohio State University College of Medicine, B311 Starling-Loving Hall, 320 West Tenth Avenue, Columbus, OH 43210-1240, USA. E-mail: belinda.avalos{at}osumc.edu

Expression of leucine-rich {alpha}2 glycoprotein (LRG), a member of the leucine-rich repeat family of proteins, was recently shown to be up-regulated during neutrophil differentiation. Its precise role in granulopoiesis, however, remains unknown. In this paper, we show that the transcription factors PU.1 and C/EBP{epsilon} that regulate the expression of multiple myeloid-specific genes also bind to the LRG promoter. We also demonstrate that LRG localizes to the same cytoplasmic compartment as myeloperoxidase and that G-CSF treatment of the 32Dcl3 myeloid cell line induces nuclear translocation of LRG. Stable transfection of LRG into 32Dcl3 cells resulted in accelerated, G-CSF-mediated neutrophil differentiation and induction of CD11b expression. In contrast, constitutive expression of LRG in 32Dwt18 cells, expressing a chimeric erythropoietin (Epo)/G-CSFR consisting of the EpoR extracellular domain fused to the G-CSFR transmembrane and cytoplasmic domains, failed to induce accelerated neutrophil differentiation and CD11b expression in response to Epo stimulation. LRG-mediated accelerated differentiation and CD11b expression were found to correlate with an increased level of phospho-Stat3 but not with PU.1 or p27kip1 levels. Hence, similar to other genes involved in neutrophil differentiation, the expression of LRG also appears to be regulated by PU.1 and C/EBP{epsilon}. Collectively, these findings suggest a role for LRG in modulating neutrophil differentiation and expression of CD11b via nonredundant G-CSFR signals.

Key Words: granulopoiesis • transcription factors






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