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Originally published online as doi:10.1189/jlb.0504286 on October 4, 2005

Published online before print October 4, 2005
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(Journal of Leukocyte Biology. 2005;78:1153-1165.)
© 2005 by Society for Leukocyte Biology

Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency

Adrian F. Gombart1, Utz Krug, James O’Kelly, Eun An, Vijaya Vegesna and H. Phillip Koeffler

Cedars-Sinai Medical Center, Division of Hematology/Oncology, Burns & Allen Research Institute and David Geffen School of Medicine at University of California Los Angeles

1Correspondence: Cedars-Sinai Medical Center, Division of Hematology/Oncology, Davis Bldg. 5019, Los Angeles, CA 90048. E-mail: gombarta{at}csmc.edu

Neutrophil-specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer-binding protein {epsilon} (C/EBPE) gene. Humans and mice lacking active C/EBP{epsilon} suffer frequent bacterial infections as a result of functionally defective neutrophils and macrophages. We hypothesized that these defects reflected dysregulation of important immune response genes. To test this, gene expression differences of peritoneally derived neutrophils and macrophages from C/EBP{epsilon}–/– and wild-type mice were determined with DNA microarrays. Of 283 genes, 146 known genes and 21 expressed sequence tags (ESTs) were down-regulated, and 85 known genes and 31 ESTs were up-regulated in the C/EBP–/– mice. These included genes involved in cell adhesion/chemotaxis, cytoskeletal organization, signal transduction, and immune/inflammatory responses. The cytokines CC chemokine ligand 4, CXC chemokine ligand 2, and interleukin (IL)-6, as well as cytokine receptors IL-8RB and granulocyte-colony stimulating factor, were down-regulated. Chromatin immunoprecipitation analysis identified binding of C/EBP{epsilon} to their promoter regions. Increased expression for lipid metabolism genes apolipoprotein E (APOE), scavenger receptor class B-1, sorting protein-related receptor containing low-density lipoprotein receptor class A repeat 1, and APOC2 in the C/EBP{epsilon}–/– mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high-fat diet. Also, C/EBP{epsilon}-deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBP{epsilon} target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.

Key Words: C/EBP{epsilon} • SGD • DNA microarray • lipid metabolism




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