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Published online before print October 4, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0504286

Received for publication May 11, 2005.
Revised June 23, 2005.
Accepted for publication July 7, 2005.

Article

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

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

^@ To whom correspondence should be addressed. E-mail: gombarta {at}csmc.edu.

	Abstract

Neutrophil-specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer-binding protein (CEBPE) gene. Humans and mice lacking active C/EBP 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-/- and wild-type mice were determined with DNA microarrays. Of 283 genes, 147 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 3, were down-regulated. Chromatin immunoprecipitation analysis identified binding of C/EBP 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-/- mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high-fat diet. Also, C/EBP-deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBP target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.

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

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