CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge.
Targeted mutation of CCAAT/enhancer binding protein (C/EBP) epsilon in mice results in early death, primarily due to spontaneous infection with Pseudomonas aeruginosa. Functional analysis of C/EBPepsilon-deficient neutrophils, in an in vivo model of peritoneal inflammation, shows multiple defects. Reduction of phagocytotic killing by C/EBPepsilon-deficient neutrophils is a result of decreased uptake of opsonized bacteria as well as little to no expression of secondary granule proteins. Abnormalities in neutrophil migration detected in a chemical peritonitis model are likely secondary to abnormal CD11b integrin and L-selectin expression on C/EBPepsilon-deficient neutrophils. Alterations in neutrophil cytokine expression in response to inflammation show decreased levels of interleukin-1 receptor antagonist (IL-1Ra) and increased levels of tumor necrosis factor-alpha (TNF-alpha) expression by C/EBPepsilon-deficient neutrophils. Additionally, TNF-alpha expression is increased in nonactivated, circulating C/EBPepsilon-deficient neutrophils. Overall, C/EBPepsilon-deficient neutrophils are severely functionally impaired, evoking an abnormal microenvironment, which may contribute to the loss of normal responses to inflammatory stimuli. Similarities between the C/EBPepsilon-deficient mouse model and the human disease, specific granule deficiency, will be discussed.
Lekstrom-Himes
J
J
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. jlekstrom@atlas.niaid.nih.gov
Xanthopoulos
K G
KG
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D019041:L-Selectin / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010529:Peritoneal Cavity; D010587:Phagocytosis; D012795:Sialoglycoproteins / Q000235:genetics; D013864:Thioglycolates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D016177:Macrophage-1 Antigen; D009687:Nuclear Proteins; D012795:Sialoglycoproteins; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin