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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 α-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.
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“RHOH expression is hardly detectable in freshly isolated human and mouse neutrophils; however, its expression is up-regulated by GM-CSF stimulation in less than 3 h (S1A Fig), confirming previously published work [27,28,38].”
From Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils (2022) · cites this paper as [38]
In the citing paper
“Of note, RHOH is a prominent gene up-regulated by GM-CSF [28,38].”
From Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils (2022) · cites this paper as [38]
In the citing paper
“Short-term in vitro exposure to GM-CSF, so-called priming, favors functional responses of neutrophils [30,57–59], while long-term stimulation with GM-CSF alters the transcriptional profile of neutrophils [28,38].”
From Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils (2022) · cites this paper as [38]
Citations
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Neutrophil granules and secretory vesicles in inflammation
Faurschou, M., & Borregaard, N. (2003) · Microbes and Infection · doi:10.1016/j.micinf.2003.09.008 · Cited by 1,162
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Metadata
- Authors
- Kobayashi, S. D., Voyich, J. M., Whitney, A. R., & DeLeo, F. R.
- Affiliations
- Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, Montana
- Venue
- Journal of Leukocyte Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-04
- Volume
- 78
- Issue
- 6
- Pages
- 1408-1418
- ISSN
- 0741-5400
- 1938-3673
- Cited by
- 148
- References
- 1
- Language
- en
- Funders
- NIH
- NIAID
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- Kobayashi, S. D., Voyich, J. M., Whitney, A. R., & DeLeo, F. R. (2005). Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor. Journal of Leukocyte Biology. https://doi.org/10.1189/jlb.0605289