Effect of granulocyte-macrophage colony-stimulating factor on sepsis- induced organ injury in rats

Abstract The administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with severe active infections has been questioned because activation of neutrophils may cause tissue injury. To identify the effect of GM-CSF administration on severe sepsis, we examined the survival rate and pathologic changes in vital organs using the rat lethal sepsis model. Rats received 20 micrograms of recombinant murine GM-CSF (rmGM-CSF) 3 hours after the onset of peritonitis induced by cecal ligation and puncture. After 48 hours, the survival rate did not improve, and earlier deaths than in the control group were observed. In addition, the inhibition of early leuko-sequestration in the peritoneal cavity was seen in animals treated with GM-CSF. These results suggested that the administration of rmGM-CSF after the onset of sepsis was not beneficial; thus, we concluded that care should be taken in the clinical use of GM-CSF in severe infection.

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Granulocyte-Macrophage Colony-Stimulating Factor inStaphylococcus aureus-Induced Arthritis

Infection and Immunity ◽

10.1128/iai.66.2.853-855.1998 ◽

1998 ◽

Vol 66 (2) ◽

pp. 853-855 ◽

Cited By ~ 4

Author(s):

Margareta Verdrengh ◽

Andrej Tarkowski

Keyword(s):

Tissue Injury ◽

Favorable Effect ◽

Protective Effects ◽

Colony Stimulating Factor ◽

Bacterial Inoculation ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

The Impact ◽

Stimulating Factor

ABSTRACT Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is able to increase not only the production of phagocytic cells but also their efficacy with respect to, e.g., bactericidal properties. In this study, we wanted to analyze the impact of GM-CSF on experimental Staphylococcus aureus-induced arthritis. For that purpose, mice were administered GM-CSF before and after bacterial inoculation. Although there was an increase in the total number of leukocytes as well as in the granulocyte fraction, there was no favorable effect on the severity of arthritis or on survival rates. There were no obvious differences between the GM-CSF-pretreated animals and controls with regard to growth of staphylococci in joints and kidneys 4 days after the bacterial inoculation. In contrast, mice that had been pretreated with GM-CSF prior to bacterial inoculation showed approximately four times lower numbers of bacteria in their blood 24 h later. These results, along with those of our previous studies, suggest that on the one hand the granulocyte is the main protective cell during the course of S. aureus infection but that on the other hand, upregulation of granulocyte-macrophage production will not exert any additional protective effects with respect to tissue injury.

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Serum Levels of Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in a Group of Patients with Systemic Sclerosis

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463209600900102 ◽

1996 ◽

Vol 9 (1) ◽

pp. 9-12 ◽

Cited By ~ 1

Author(s):

A. Riccio ◽

M. De Caterina ◽

D. Natale ◽

E. Grimaldi ◽

G. Pronesti ◽

...

Keyword(s):

Systemic Sclerosis ◽

Clinical Manifestations ◽

Serum Levels ◽

Control Group ◽

Age Group ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

In this report we investigate the behaviour of the serum levels of Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in the course of Systemic Sclerosis (SS). This cytokine is produced mainly by T and NK cells, and its possible role in the pathogenesis of SS has not been previously described in the literature. Serum GM-CSF levels were assayed in 10 female patients, ageing from 35 to 70, affected by SS. These patients were not suffering from other disorders and were not being treated with steroids or immunosuppressive drug. A solid phase immunoenzymatic method was used to assess the serum levels of GM-CSF. Reference values were previously determined in a control group of 36 healthy women blood donors (19 premenopausal and 17 postmenopausal) (x̄=20.1 ±12.3 pg/ml). All the patients but one showed significantly increased serum levels of GM-CSF (x̄= 120.9 ±125.5 pg/ml). The highest levels were found in the two oldest patients, who also had the longest clinical history of SS, but a clear correlation with age, disease duration or clinical manifestations was not evident, even if the postmenopausal age group patients showed a higher mean value of GM-CSF (x̄= 148.0±144.1 pg/ml) than that found in the premenopausal age group (x̄= 57.7±1.4 pg/ml) (in contrast with the findings in the control group). The absence of other pathogenic conditions in our patients suggests that the increase in serum levels of GM-CSF might be linked to the fibroblast proliferation which is typical of SS. However, our results do not explain the role played by this factor in the fibroblastic proliferation process and an in vitro study is necessary to clarify this aspect.

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Effects of continuous localized infusion of granulocyte—macrophage colony—stimulating factor and inoculations of irradiated glioma cells on tumor regression

Journal of Neurosurgery ◽

10.3171/jns.1999.90.6.1064 ◽

1999 ◽

Vol 90 (6) ◽

pp. 1064-1071 ◽

Cited By ~ 29

Author(s):

Margaret A. Wallenfriedman ◽

John A. Conrad ◽

Lance DelaBarre ◽

Patrick C. Graupman ◽

Gina Lee ◽

...

Keyword(s):

Brain Tumors ◽

Tumor Antigens ◽

Control Group ◽

Colony Stimulating Factor ◽

Content Type ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Fine Print

Object. Glioblastoma multiforme (GBM) is a malignant tumor of the central nervous system that directly suppresses immunological defenses in vitro and in vivo. The authors used the peripheral delivery of continuously infused granulocyte—macrophage colony-stimulating factor (GM-CSF) in the presence of irradiated tumor antigens as a tumor-specific stimulant to dendritic cells to initiate an immune response to GBM in rats.Methods. The 9L gliosarcoma tumors were established in the flanks of syngeneic Fischer 344 rats. Osmotic minipumps implanted in the animals' contralateral flanks continuously delivered recombinant GM-CSF (0, 0.1, 1, or 10 ng/day) for 28 days. Irradiated gliosarcoma cells were intermittently injected at the site of the GM-CSF infusion. Animals in the saline control group (0 ng/day GM-CSF) died on Day 59 with average tumor volumes greater than 30,000 mm3. This control group was significantly different from the GM-CSF—treated animals, which all survived with average tumor volumes that peaked on Day 23 and later regressed completely. Tumor growth as well as peak tumor volumes (5833 ± 2284 mm3, 3294 ± 1632 mm3, and 1979 ± 1142 mm3 for 0.1, 1, and 10 ng/day GM-CSF, respectively) in the different treatment groups reflected a significant dose-response relationship with the GM-CSF concentrations. All animals treated with GM-CSF and irradiated cells were resistant to additional challenges of peripheral and intracerebral gliosarcoma, even when they were inoculated 8 months after initial immunotherapy. The colocalization of GM-CSF and inactivated tumor antigens was required to stimulate immunoprotection. To test the efficacy of a peripherally administered immunological therapy on intracerebral brain tumors the authors transplanted 106 gliosarcoma cells into the striatum of treated and control animals. Subcutaneous pumps that released GM-CSF (10 ng/day) and irradiated gliosarcoma cells were placed in the treated animals. The control animals all died within 31 days after intracerebral tumor implantation. In contrast, 40% of the animals receiving GM-CSF—irradiated cell vaccinations survived beyond 300 days. These long-term survivors showed no evidence of gliosarcoma at the injection site on evaluation by magnetic resonance imaging.Conclusions. These results suggest that the continuous localized delivery of subcutaneous GM-CSF in conjunction with inactivated tumor antigens can initiate a systemic response that leads to the regression of distant peripheral and intracerebral tumors. The success of this treatment illustrates the feasibility of tumor-specific peripheral immunological stimulation after tumor resection to prevent the recurrence of malignant brain tumors.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies treatment for COVID-19 patients: a meta-analysis

10.1101/2022.01.07.22268878 ◽

2022 ◽

Author(s):

JinTao Guan ◽

Anran Xi ◽

DU Jin ◽

XiaoYue Mou ◽

Zhenghao Xu

Keyword(s):

Meta Analysis ◽

Invasive Mechanical Ventilation ◽

Random Effect Model ◽

Cochrane Library ◽

Control Group ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Objective: We performed a meta analysis in order to determine safety of granulocyte macrophage colony stimulating factor (GM CSF) antibodies on COVID 19. Methods: We searched from the Cochrane Library, PubMed, Embase, biorxiv and medrxiv databases beginning in the COVID-19 outbreak on December 1, 2019 until August 29, 2021. The primary outcomes included death, the incidence of invasive mechanical ventilation (IMV), ventilation requirement, and secondary infection. Results: 6 eligible literature involving 1501 COVID 19 patients were recruited, and they were divided into experimental group (n = 736) and control group (n = 765). Using a random effect model, we found that the GM CSF antibodies treatment was associated with a 3.8-26.9% decline of the risk of mortality[odd ratio (OR) = 0.06, 95% confidence interval (CI): -0.11, -0.01, p =0.02], a 5.3-28.7% reduction of incidence of IMV [OR = 0.51, 95% CI: 0.28, 0.95, p =0.03], and a 23.3-50.0% enhancement of ventilation improvement [OR = 11.70, 95% CI: 1.99, 68.68, p=0.006]. There were no statistically significant differences in the association between two groups in second infection. Conclusion: Severe COVID 19 patients may benefit from GM CSF antibodies.

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Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors

Scientific Reports ◽

10.1038/s41598-021-84249-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jani Lappalainen ◽

Nicolas Yeung ◽

Su D. Nguyen ◽

Matti Jauhiainen ◽

Petri T. Kovanen ◽

...

Keyword(s):

Expression Profiles ◽

Gene Expression Profiles ◽

Foam Cells ◽

Colony Stimulating Factor ◽

Human Macrophages ◽

Gm Csf ◽

Macrophage Subpopulations ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

AbstractIn atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte–macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

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Growth stimulation of non-small cell lung cancer xenografts by granulocyte-macrophage colony-stimulating factor (GM-CSF)

European Journal of Cancer ◽

10.1016/s0959-8049(98)00236-6 ◽

1998 ◽

Vol 34 (12) ◽

pp. 1958-1961 ◽

Cited By ~ 15

Author(s):

Y. Oshika ◽

M. Nakamura ◽

Y. Abe ◽

Y. Fukuchi ◽

M. Yoshimura ◽

...

Keyword(s):

Lung Cancer ◽

Growth Stimulation ◽

Small Cell ◽

Colony Stimulating Factor ◽

Small Cell Lung ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Stimulation Of

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The Truncated Splice Variant of the Granulocyte-Macrophage-Colony-Stimulating Factor Receptor β- Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns

Neonatology ◽

10.1159/000513356 ◽

2021 ◽

pp. 1-7

Author(s):

Verena Schulte ◽

Alexandra Sipol ◽

Stefan Burdach ◽

Esther Rieger-Fackeldey

Keyword(s):

Respiratory Failure ◽

Peripheral Blood ◽

Colony Stimulating Factor ◽

Term Infants ◽

Respiratory Impairment ◽

Gm Csf ◽

A Subunit ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Background: The granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays an important role in surfactant homeostasis. βC is a subunit of the GM-CSF receptor (GM-CSF-R), and its activation mediates surfactant catabolism in the lung. βIT is a physiological, truncated isoform of βC and is known to act as physiological inhibitor of βC. Objective: The aim of this study was to determine the ratio of βIT and βC in the peripheral blood of newborns and its association with the degree of respiratory failure at birth. Methods: We conducted a prospective cohort study in newborns with various degrees of respiratory impairment at birth. Respiratory status was assessed by a score ranging from no respiratory impairment (0) to invasive respiratory support (3). βIT and βC expression were determined in peripheral blood cells by real-time PCR. βIT expression, defined as the ratio of βIT and βC, was correlated with the respiratory score. Results: βIT expression was found in all 59 recruited newborns with a trend toward higher βIT in respiratory ill (score 2, 3) newborns than respiratory healthy newborns ([score 0, 1]; p = 0.066). Seriously ill newborns (score 3) had significantly higher βIT than healthy newborns ([score 0], p = 0.010). Healthy preterm infants had significantly higher βIT expression than healthy term infants (p = 0.019). Conclusions: βIT is expressed in newborns with higher expression in respiratory ill than respiratory healthy newborns. We hypothesize that βIT may have a protective effect in postnatal pulmonary adaptation acting as a physiological inhibitor of βC and, therefore, maintaining surfactant in respiratory ill newborns.

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Identification through chemical cross-linking of distinct granulocyte- macrophage colony-stimulating factor and interleukin-3 receptors on myeloid leukemic cells, KG-1

Blood ◽

10.1182/blood.v74.8.2652.2652 ◽

1989 ◽

Vol 74 (8) ◽

pp. 2652-2656 ◽

Cited By ~ 23

Author(s):

T Gesner ◽

RA Mufson ◽

KJ Turner ◽

SC Clark

Keyword(s):

Binding Proteins ◽

Myelogenous Leukemia ◽

Cross Linking ◽

Colony Stimulating Factor ◽

Interleukin 3 ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Chemical Cross Linking

Abstract Granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) each bind specifically to a small number of high- affinity receptors present on the surface of the cells of the acute myelogenous leukemia line, KG-1. Through chemical cross-linking of IL-3 and GM-CSF to KG-1 cells, we identified distinct binding proteins for each of these cytokines with approximate molecular masses of 69 and 93 Kd, respectively. Although these two binding proteins are distinct, GM- CSF and IL-3 compete with each other for binding to KG-1 cells. Other cell lines, which express receptors for either factor but not for both do not display this cross-competition for binding with IL-3 and GM-CSF. These findings imply that distinct IL-3 and GM-CSF binding proteins are expressed on the cell surface and that an association exists between these proteins on KG-1 cells.

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Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes

Blood ◽

10.1182/blood.v88.4.1206.bloodjournal8841206 ◽

1996 ◽

Vol 88 (4) ◽

pp. 1206-1214 ◽

Cited By ~ 70

Author(s):

RL Rosen ◽

KD Winestock ◽

G Chen ◽

X Liu ◽

L Hennighausen ◽

...

Keyword(s):

Molecular Weight ◽

Human Peripheral Blood ◽

Janus Kinase ◽

Lower Molecular Weight ◽

Colony Stimulating Factor ◽

Enhancer Element ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway. Recent studies have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5. To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage- CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms. Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule. Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element. Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A. STAT5A-STAT5A homodimers and STAT5A- STAT5B heterodimers formed in response to GM-CSF. Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR. Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF.

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