The addition of granulocyte macrophage colony stimulating factor (GM-CSF) to juvenile systemic lupus erythematosus serum can reduce abnormal neutrophil apoptosis

Recombinant human granulocyte colony-stimulating factor (G-CSF) is commonly used to accelerate recovery of neutropenia in patients with marrow suppression. We hereby report a patient with systemic lupus erythematosus (SLE) who developed diffuse lupus nephritis and impending cytokine storm after G-CSF therapy. The exact mechanisms by which G-CSF leads to lupus flares remains enigmatic. Increased neutrophil apoptosis and release of cytokines have been postulated. The use of G-CSF in patients with autoimmune disease should be cautious.

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The diadenosine polyphosphates Ap3A and Ap4A and adenosine triphosphate interact with granulocyte-macrophage colony-stimulating factor to delay neutrophil apoptosis: implications for neutrophil: platelet interactions during inflammation

Blood ◽

10.1182/blood.v87.8.3442.bloodjournal8783442 ◽

1996 ◽

Vol 87 (8) ◽

pp. 3442-3449 ◽

Cited By ~ 32

Author(s):

L Gasmi ◽

AG McLennan ◽

SW Edwards

Keyword(s):

Adenosine Triphosphate ◽

Immune Cell ◽

Cellular Morphology ◽

Neutrophil Apoptosis ◽

Colony Stimulating Factor ◽

Diadenosine Polyphosphates ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Incubation of neutrophils with cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) delays their loss of function and changes in cellular morphology that are characteristic of apoptosis. Adenosine triphosphate (ATP) and the diadenosine polyphosphates Ap4A and AP3A were almost as effective as GM-CSF in delaying neutrophil apoptosis. The nucleotides could thus preserve cellular morphology, protect against chromatin fragmentation, and preserve functions such as NADPH oxidase activity and expression of CD16. Moreover, addition of ATP, AP3A and AP4A together with GM-CSF resulted in more pronounced protection from apoptosis than was observed during incubation with either the cytokine or the nucleotides alone. Because ATP, Ap3A, and AP4A may be secreted from activated platelets, these observations suggest that platelet-derived products, perhaps acting in combination with endothelial-derived or immune cell-derived cytokines, can regulate neutrophil function during certain types of inflammation.

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Toxoplasma gondii Induces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis

Infection and Immunity ◽

10.1128/iai.70.11.6048-6057.2002 ◽

2002 ◽

Vol 70 (11) ◽

pp. 6048-6057 ◽

Cited By ~ 22

Author(s):

Jacqueline Y. Channon ◽

Kristin A. Miselis ◽

Laurie A. Minns ◽

Chaitali Dutta ◽

Lloyd H. Kasper

Keyword(s):

Conditioned Medium ◽

Human Fibroblasts ◽

Neutrophil Apoptosis ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Soluble Mediator ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

ABSTRACT Human neutrophils are rescued from apoptosis following incubation with once-washed, fibroblast-derived Toxoplasma gondii tachyzoites. Both infected and uninfected neutrophils are rescued, implicating a soluble mediator. In this study we investigated the origin and identity of this soluble mediator. Neutrophils were incubated either with purified tachyzoites or with conditioned medium derived from T. gondii-infected human fibroblasts. Conditioned medium was found to be a potent stimulus that delayed neutrophil apoptosis up to 72 h, whereas purified and extensively washed tachyzoites had no effect. Delayed apoptosis correlated with up-regulation of the neutrophil antiapoptotic protein, Mcl-1, and the neutrophil interleukin 3 receptor α subunit (IL-3Rα), suggesting a role for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF and granulocyte colony-stimulating factor (G-CSF) were measurable in conditioned medium by enzyme-linked immunosorbent assay. Neutralizing antibodies to GM-CSF and G-CSF were additive in abrogating delayed neutrophil apoptosis induced by conditioned medium. Inhibitors of Src family tyrosine kinases, Gi proteins, phosphatidylinositol 3-kinase, p44 erk1 and p42 erk2 mitogen-activated protein kinases, and Jak2 kinases partially attenuated the effect of conditioned medium, consistent with a role for G-CSF and/or GM-CSF. Hence, delayed neutrophil apoptosis is mediated by GM-CSF and G-CSF secreted by T. gondii-infected human fibroblasts. This enhanced neutrophil survival may contribute to the robust proinflammatory response elicited in the T. gondii-infected host.

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Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis

Mediators of Inflammation ◽

10.1080/09629359890767 ◽

1998 ◽

Vol 7 (6) ◽

pp. 391-396 ◽

Cited By ~ 8

Author(s):

Cosimo Tortorella ◽

Giuseppina Piazzolla ◽

Felice Spaccavento ◽

Salvatore Antonaci

Keyword(s):

Cyclic Amp ◽

Camp Signaling ◽

Neutrophil Apoptosis ◽

Colony Stimulating Factor ◽

Dibutyryl Camp ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Neutrophil Survival ◽

Stimulating Factor

The current study was undertaken to evaluate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclic AMP (cAMP) signaling interaction on human neutrophil apoptosis, either occurring spontaneously or induced by Fas antigen activation. Results show that GM-CSF, dibutyryl cAMP (a cAMP analog) and forskolin (an adenylate cyclase activator) are all able to suppress spontaneous neutrophil cell death. Of note however, when GM-CSF is used in combination with cAMP-elevating agents, an additive effect on neutrophil survival is observed with dibutyryl cAMP only, whereas supplementation of cell cultures with GM-CSF and forskolin results in a progressive reduction of antiapoptotic effects exerted by the single compounds. Moreover, although dibutyryl cAMP and forskolin do not affect Fas-triggered apoptotic events, they are still able to modulate the GM-CSF capacity to prolong neutrophil survival following anti-Fas IgM cell challenge, with effects similar to those respectively exerted on spontaneous neutrophil apoptosis. The data indicate that GM-CSF m ay negatively modulate the cAMP-mediated antiapoptotic pathway in human neutrophils, likely via the inhibition of adenylate cyclase activity. This would prevent an abnormal neutrophil survival as a result of cAMP signaling stimulation, which provides a novel insight into the role of GM-CSF as a physiological regulator of myeloid cell turnover.

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Application of Western Blot for detection of neutrophil apoptosis-related proteins

Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis ◽

10.11118/actaun200957010097 ◽

2009 ◽

Vol 57 (1) ◽

pp. 97-104

Author(s):

Petr Sláma

Keyword(s):

Western Blot ◽

Myeloid Cell ◽

Neutrophil Apoptosis ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Western Blot Method ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Related Proteins ◽

Stimulating Factor

The aim of this study was to evaluate suitability of using Western Blot for detection of neutrophil apoptosis and neutrophil apoptosis-related proteins, respectively. Neutrophils were isolated from blood of healthy adult donors and incubated with G-CSF (granulocyte colony stimulating factor), GM-CSF (granulocyte-macrophage colony stimulating factor), ATP (adenosine triphosphate) and FMLP (N-formyl-methionyl-leucyl-phenylalanine). The neutrophils were incubated 4, 8 and 20 hours at 37 °C. In this assay, an expression of Mcl-1 (myeloid cell leukemia 1), XIAP (X-linked inhibitor of apoptosis) and gelsolin was analysed by Western Blot method. The results showed that Western Blot is a suitable method for detection of neutrophil apoptosis-related proteins and detection of neutrophil apoptosis, respectively.

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The protective effect of GM-CSF on serum-induced neutrophil apoptosis in juvenile systemic lupus erythematosus patients

Clinical Rheumatology ◽

10.1007/s10067-014-2800-2 ◽

2014 ◽

Vol 34 (1) ◽

pp. 85-91 ◽

Cited By ~ 15

Author(s):

Direkrit Chiewchengchol ◽

Angela Midgley ◽

Pimpayao Sodsai ◽

Tawatchai Deekajorndech ◽

Nattiya Hirankarn ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Protective Effect ◽

Lupus Erythematosus ◽

Neutrophil Apoptosis ◽

Systemic Lupus ◽

Juvenile Systemic Lupus Erythematosus ◽

Gm Csf

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The dual effects of TNFα on neutrophil apoptosis are mediated via differential effects on expression of Mcl-1 and Bfl-1

Blood ◽

10.1182/blood-2007-05-087833 ◽

2008 ◽

Vol 111 (2) ◽

pp. 878-884 ◽

Cited By ~ 60

Author(s):

Andrew Cross ◽

Robert J. Moots ◽

Steven W. Edwards

Keyword(s):

Inflammatory Diseases ◽

Neutrophil Apoptosis ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Low Concentrations ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Opposing Effects ◽

Neutrophil Survival ◽

Stimulating Factor

Neutrophils have a very short half-life in the circulation, undergoing rapid death by apoptosis, but a number of agents can either delay or accelerate the rate at which these cells undergo death. TNFα can exert opposing, concentration-dependent effects on neutrophils to either accelerate their apoptosis or enhance their survival. We show that TNFα greatly increases the rate of turnover of Mcl-1, an antiapoptotic protein that plays a key role in neutrophil survival. In contrast to Mcl-1 turnover in control- or granulocyte-macrophage colony-stimulating factor (GM-CSF)–treated neutrophils that occurs via the proteasome, TNFα-accelerated Mcl-1 turnover occurs via activation of caspases. Mcl-1–depleted cells thus have accelerated rates of apoptosis. While TNFα had no effect on MCL-1 transcription, it induced expression of another antiapoptotic molecule, BFL-1. Low concentrations of TNFα (≤ 1 ng/mL) stimulated BFL-1 expression, whereas higher concentrations (≥ 10 ng/mL) triggered caspase-dependent acceleration of Mcl-1 turnover. These opposing effects on 2 separate antiapoptotic systems of neutrophils explain the divergent effects of TNFα on neutrophil apoptosis and have important implications for understanding how TNFα may affect immune function in inflammatory diseases.

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