title: Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor.
abstract: Polymorphonuclear leukocytes (PMNs or neutrophils) are the most prominent cellular component of the innate immune system in humans and produce an array of potent cytotoxic molecules. It is important that neutrophils undergo constitutive (spontaneous) apoptosis as a mechanism to facilitate normal cell turnover and immune system homeostasis. Conversely, several proinflammatory cytokines, including granulocyte macrophage-colony stimulating factor (GM-CSF), prolong neutrophil survival. The molecular mechanisms that regulate PMN apoptosis or survival remain incompletely defined. To that end, we compared global gene expression in human neutrophils during spontaneous apoptosis with that in cells cultured with human GM-CSF. Genes encoding proteins that inhibit apoptosis, such as myeloid cell leukemia sequence 1, caspase 8 and Fas-associated via death domain-like apoptosis regulator (CFLAR), B cell chronic lymphocytic leukemia/lymphoma 2 (BCL2)/adenovirus E1B 19 kDa-interacting protein 2 (BNIP2), and serum/glucocorticoid-regulated kinase (SGK), were down-regulated coincident with neutrophil apoptosis. In contrast, those encoding apoptosis inhibitor 5, BCL2-like 1, BNIP2, CFLAR, SGK, and tumor necrosis factor alpha-induced protein 8 were up-regulated in PMNs cultured with GM-CSF. Correspondingly, GM-CSF delayed PMN apoptosis (P<0.03), increased cell viability (P<0.03), and prolonged neutrophil phagocytic capacity (P<0.05). Prolonged functional capacity was paralleled by striking up-regulation of proinflammatory genes and proteins, including CD14, CD24, CD66, and human leukocyte antigen-DR. In addition, expression of SGK protein diminished during PMN apoptosis but was restored by culture with GM-CSF, suggesting SGK is involved in leukocyte survival. These studies provide a global view of the molecular events that regulate neutrophil survival and apoptosis.
authors.affiliation: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kobayashi
authors.forename: Jovanka M
authors.initials: JM
authors.lastname: Voyich
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Whitney
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017874:Immediate-Early Proteins; D018836:Inflammation Mediators; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D000099184:Serum-Glucocorticoid Regulated Kinases