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1.
2.
In this work we provide evidence showing that granulocytes produce macrophage colony-stimulating factor (M-CSF) from the band cell stage and secrete this factor when induced to differentiate into polymorphonuclear cells by recombinant human granulocyte colony-stimulating factor (rhG-CSF). Using an enriched population of myeloid band cells from murine bone marrow, we identified the presence of M-CSF with a chromophore-labelled monoclonal anti-M-CSF antibody. Using ELISA we detected the secretion of M-CSF in the supernatants of cultures of enriched band cells when induced with rhG-CSF to differentiate into mature neutrophils. We also found that M-CSF is the only factor responsible for the colony forming activity in the supernatants and lysates of band cells treated with rhG-CSF.  相似文献   

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Granulocyte colony-stimulating factor promotes adhesion of neutrophils   总被引:2,自引:0,他引:2  
Granulocyte colony stimulating factor(G-CSF) is well known for its ability to drive the maturation andmobilization of neutrophils. G-CSF also appears to have the potentialto activate functions of mature neutrophils, influencing recruitment atsites of inflammation and tissue injury. We investigated the ability ofG-CSF to stimulate adhesion of isolated blood neutrophils. G-CSFinduced significant adherence to intercellular adhesion molecule(ICAM)-1 that was both macrophage antigen-1 (Mac-1) and leukocytefunction-associated antigen-1 dependent. The kinetics ofG-CSF-stimulated adhesion to ICAM-1 peaked at 11 min without detectablesurface upregulation of Mac-1. This was in marked contrast tochemokines, in which peak activation of adhesion is seen within 1 minof stimulation. In contrast to chemokine-induced adhesion, G-CSFstimulation was not inhibited by pertussis toxin. G-CSF also augmentedthe attachment of neutrophils to activated human umbilical veinendothelial cells (HUVEC) through specific effects on neutrophils,because HUVEC appear to lack functional G-CSF receptors.

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5.
The granulocyte colony-stimulating factor (G-CSF) belongs to a family of hemopoietic growth factors regulating the production of granulocytes and macrophages. Murine G-CSF stimulates the proliferation and differentiation of precursors of neutrophilic granulocytes and is also able to stimulate the functional activities of mature neutrophils. Among the hemopoietic growth factors, G-CSF has an outstanding capacity to induce terminal differentiation and suppression of self-renewal in myeloid leukemic cells. Murine and human G-CSF's show complete biological cross-reactivity across species and bind equally well to G-CSF receptors of either species. Specific receptors for G-CSF exist on all normal neutrophilic cells and have not been lost in the generation of primary human myeloid leukemias. This data indicates that G-CSF may be a useful reagent in the treatment of myeloid leukemia, in hemopoietic regeneration and in increasing resistance against infections.  相似文献   

6.
Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 microgram. kg(-1). day(-1) subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.  相似文献   

7.
Hermesh T  Moran TM  Jain D  López CB 《PloS one》2012,7(5):e37334
A burst in the production of pro-inflammatory molecules characterizes the beginning of the host response to infection. Cytokines, chemokines, and growth factors work in concert to control pathogen replication and activate innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF) mobilizes and activates hematopoietic cells from the bone marrow, and it has been shown to mediate the generation of effective immunity against bacterial and fungal infections. G-CSF is produced at high levels in the lungs during infection with influenza and parainfluenza viruses, but its role during these infections is unknown. Here we show that during infection of mice with a non-lethal dose of influenza or Sendai virus, G-CSF promotes the accumulation of activated Ly6G+ granulocytes that control the extent of the lung pro-inflammatory response. Remarkably, these G-CSF-mediated effects facilitate viral clearance and sustain mouse survival.  相似文献   

8.
Pretreatment with recombinant human granulocyte CSF (G-CSF) protected mice in two different models of septic shock. Intravenous injection of 250 micrograms/kg G-CSF to mice prevented lethality induced by 5 mg/kg LPS. Injection of 50 micrograms/kg G-CSF protected galactosamine-sensitized mice against LPS-induced hepatitis. In either case, this protection was accompanied by a suppression of LPS-induced serum TNF activity. In contrast, when galactosamine-sensitized mice were pretreated with 50 micrograms/kg murine recombinant granulocyte/macrophage CSF instead of G-CSF and subsequently challenged with LPS, serum TNF activity was significantly enhanced and mortality was increased. The suppressive effect of G-CSF on LPS-induced TNF production was also demonstrated in rats. In vivo, no TNF was detectable in the blood of LPS-treated rats, which had been pretreated with G-CSF. Ex vivo, alveolar macrophages, bone marrow macrophages, Kupffer cells, or peritoneal macrophages prepared from G-CSF-treated rats produced significantly less TNF upon stimulation with LPS than corresponding populations from control rats. However, when these macrophage populations were incubated with G-CSF in vitro, LPS-induced TNF production was unaffected. These data suggest that the G-CSF-mediated suppression of TNF production is not a direct effect of G-CSF on macrophages. To examine whether, independent of the protection against LPS, G-CSF treatment still activated neutrophils, it was demonstrated that granulocytes from G-CSF-treated rats were primed for PMA-induced oxidative burst and for ionophore/arachidonic acid-stimulated lipoxygenase product formation. The experiments of this study support the notion that G-CSF is a negative feedback signal for macrophage-derived TNF-alpha production during Gram-negative sepsis.  相似文献   

9.

Background

Exposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colony-stimulating factor (G-CSF) is the only treatment recommended to be given to radiation victims soon after IR. However, clinical studies have shown that G-CSF used to treat the leukopenia induced by radiotherapy or chemotherapy in patients can cause sustained low white blood cell counts in peripheral blood. It has been suggested that this adverse effect is caused by HSC and hematopoietic progenitor cell (HPC) proliferation and differentiation stimulated by G-CSF, which impairs HSC self-renewal and may exhaust the BM capacity to exacerbate IR-induced LT-BM injury.

Methods

C57BL/6 mice were exposed to 4 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 1.08 Gy per minute, and the mice were treated with G-CSF (1 μg/each by ip) or vehicle at 2 and 6 h after TBI on the first day and then twice every day for 6 days. All mice were killed one month after TBI for analysis of peripheral blood cell counts, bone marrow cellularity and long-term HSC (CD34-lineage-sca1+c-kit+) frequency. The colony-forming unit-granulocyte and macrophage (CFU-GM) ability of HPC was measured by colony-forming cell (CFC) assay, and the HSC self-renewal capacity was analyzed by BM transplantation. The levels of ROS production, the expression of phospho-p38 mitogen-activated protein kinase (p-p38) and p16INK4a (p16) mRNA in HSCs were measured by flow cytometry and RT-PCR, respectively.

Results

The results of our studies show that G-CSF administration mitigated TBI-induced decreases in WBC and the suppression of HPC function (CFU-GM) (p < 0.05), whereas G-CSF exacerbated the suppression of long-term HSC engraftment after transplantation one month after TBI (p < 0.05); The increase in HSC damage was associated with increased ROS production, activation of p38 mitogen-activated protein kinase (p38), induction of senescence in HSCs.

Conclusion

Our findings suggest that although G-CSF administration can reduce ARS, it can also exacerbate TBI-induced LT-BM injury in part by promoting HSC senescence via the ROS-p38-p16 pathway.
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10.
The granulocyte colony-stimulating factor receptor (G-CSFR) plays an important role in the production, survival and activation of neutrophilic granulocytes during both normal and emergency hematopoiesis. The G-CSFR also participates in the development of other myeloid lineages, the mobilization of hematopoietic stem cells and myeloid cell migration. This has lead to several important clinical applications for its ligand, G-CSF. More recently, additional important roles for G-CSFR have emerged outside the hematopoietic system, such as in the protection and repair of a diverse range of tissues, including muscle, liver and neural tissue, providing further scope for developing G-CSF as a therapeutic agent. The G-CSFR has also been implicated in the etiology of disease, with mutations/variants of G-CSFR implicated in neutropenia, myelodysplasia and leukemia. Additionally, autocrine/paracrine stimulation of G-CSFR may be important in the biology of solid tumors, including metastasis.  相似文献   

11.
Granulocyte colony-stimulating factor: a novel mediator of T cell tolerance   总被引:7,自引:0,他引:7  
In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.  相似文献   

12.
Previously, we suggested that the phosphatidylinositol 3-kinase (PI3K)-p70 S6 kinase (p70 S6K) pathway plays an important role in granulocyte colony-stimulating factor (G-CSF)-dependent enhancement of the neutrophilic differentiation and proliferation of HL-60 cells. While atypical protein kinase C (PKC) has been reported to be a regulator of p70 S6K, abundant expression of PKCiota was observed in myeloid and lymphoid cells. Therefore, we analyzed the participation of PKCiota in G-CSF-dependent proliferation. The maximum stimulation of PKCiota was observed from 15 to 30 min after the addition of G-CSF. From 5 to 15 min into this lag time, PKCiota was found to translocate from the nucleus to the membrane. At 30 min it re-translocated to the cytosol. This dynamic translocation of PKCiota was also observed in G-CSF-stimulated myeloperoxidase-positive cells differentiated from cord blood cells. Small interfering RNA for PKCiota inhibited G-CSF-induced proliferation and the promotion of neutrophilic differentiation of HL-60 cells. These data indicate that the G-CSF-induced dynamic translocation and activation processes of PKCiota are important to neutrophilic proliferation.  相似文献   

13.
We studied the effect of G-CSF on TLR agonist-induced cytokine production in human neutrophils. Human neutrophils produced IL-8 and TNF-α in response to stimulation with TLR agonists such as LPS and N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine. This response was dependent on activation of ERK, p38, and PI3K, but not JNK. TLR agonist-induced cytokine production in neutrophils was inhibited by G-CSF, whereas it was enhanced by GM-CSF, and GM-CSF-mediated enhancement was attenuated by G-CSF. G-CSF and GM-CSF did not affect TLR agonist-induced phosphorylation of ERK, p38, JNK, Akt, and IκBα. STAT3 activation was much greater in G-CSF-stimulated neutrophils than that in GM-CSF-stimulated cells. G-CSF-mediated STAT3 phosphorylation and inhibition of TLR agonist-induced cytokine production were prevented by pretreatment of cells with AG-490 (JAK2 inhibitor). These findings suggest that G-CSF and GM-CSF exert the opposite effects on TLR agonist-induced cytokine production, and G-CSF negatively regulates TLR agonist-induced cytokine production in neutrophils via activation of STAT3.  相似文献   

14.
Abstract Granulocyte colony-stimulating factor (G-CSF) stimulates a subset of granulocyte colony forming cells and when administered to neutropenic individuals results in recovery of blood neutrophil numbers to normal levels. Therefore, G-CSF may be a useful therapeutic agent for infections in immunocompromised hosts. However, to date there has been only limited information that G-CSF activates the antimicrobial activity of neutrophils. In the present study, we found that recombinant G-CSF promotes the anti- Candida albicans activity of normal human blood polymorphonuclear (PMN) cells in vitro using both a 3H-glucose uptake procedure and a Candida colony counting assay. As little as 0.1 ng/ml G-CSF induced significant anti-Candida activity in the PMN cultures. G-CSF treatment also enhanced superoxide anion production by the PMNs in response to f-MLP as determined by the superoxide dismutase inhibitable cytochrome C reduction method. Such results show that G-CSF can promote the antimicrobial activity of peripheral blood PMNs against C. albicans .  相似文献   

15.
Hematopoiesis, the process of blood cell formation, is orchestrated by cytokines and growth factors that stimulate the expansion of different progenitor cell subsets and regulate their survival and differentiation into mature blood cells. Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic growth factor involved in the control of neutrophil development. G-CSF is now applied on a routine basis in the clinic for treatment of congenital and acquired neutropenias. G-CSF activates a receptor of the hematopoietin receptor superfamily, the G-CSF receptor (G-CSF-R), which subsequently triggers multiple signaling mechanisms. Here we review how these mechanisms contribute to the specific responses of hematopoietic cells to G-CSF and how perturbations in the function of the G-CSF-R are implicated in various types of myeloid disease.  相似文献   

16.
We investigated the capacity of mouse Langerhans cells (LC) to produce IL-12, a central cytokine in a Th1 type of immune responses. We prepared purified LC (>95%) from BALB/c mouse skin by the panning method using anti-I-Ad mAb. An ELISA showed that purified LC spontaneously produced IL-12 p40, and that its production was up-regulated following simultaneous stimulation with anti-CD40 mAb and IFN-gamma. Surprisingly, GM-CSF strikingly inhibited IL-12 p40 production by anti-CD40/IFN-gamma-stimulated LC (% inhibition = 97.0 +/- 0.9% at 1 ng/ml GM-CSF). Supernatants of 48-h cultured keratinocytes (KC) also caused the inhibition of LC IL-12 p40 secretion, and this effect was neutralized by anti-GM-CSF mAb. IL-1alpha (1 ng/ml)-stimulated KC produced much more GM-CSF than unstimulated KC (60.9 +/- 0.2 pg/ml vs 20.9 +/- 1.7 pg/ml), and IL-1alpha-stimulated KC supernatants strongly inhibited IL-12 p40 production by anti-CD40/IFN-gamma-stimulated LC (% inhibition = 89.4 +/- 1.4%). A bioassay using an IL-12-dependent T cell line demonstrated the correlation of the level of IL-12 p40 with the bioactivity of IL-12. These results provide important implications for the pathogenesis of atopic dermatitis, which involves the participation of LC and KC with the capacity to produce IL-12 and GM-CSF, respectively.  相似文献   

17.
The purpose of this study was to determine whether human polymorphonuclear neutrophils (PMN), which share a common cell lineage with macrophages, could produce factors such as IL-1. We show by Northern blot analysis and bioassays that PMN can be induced to accumulate mRNA specific for IL-1 alpha and IL-1 beta indistinguishable in size from IL-1 mRNA synthesized by activated human macrophages and consequently to release IL-1-like activity in their culture supernatants, that could be neutralized by a mAb to IL-1. The granulocyte-macrophage colony-stimulating factor was identified as a major physiologic inducer for PMN-IL-1.  相似文献   

18.
Chronic alcohol abuse increases the risk of developing acute lung injury approximately threefold in septic patients, and ethanol ingestion for 6 wk in rats impairs alveolar epithelial barrier function both in vitro and in vivo. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a trophic factor for the alveolar epithelium, and a recent phase II clinical study suggests that GM-CSF therapy decreases sepsis-mediated lung injury. Therefore, we hypothesized that GM-CSF treatment could improve ethanol-mediated defects in the alveolar epithelium during acute stresses such as endotoxemia. In this study, we determined that recombinant rat GM-CSF improved lung liquid clearance (as reflected by lung tissue wet:dry ratios) in ethanol-fed rats anesthetized and then challenged with 2 ml of saline via a tracheostomy tube. Furthermore, GM-CSF treatment improved lung liquid clearance and decreased epithelial protein leak in both control-fed and ethanol-fed rats after 6 h of endotoxemia induced by Salmonella typhimurium lipopolysaccharide given intraperitoneally, but with the greater net effect seen in the ethanol-fed rats. Our previous studies indicate that chronic ethanol ingestion decreases lung liquid clearance by increasing intercellular permeability. Consistent with this, GM-CSF treatment in vitro decreased permeability of alveolar epithelial monolayers derived from both control-fed and ethanol-fed rats. As in the endotoxemia model in vivo, the effect of GM-CSF was most dramatic in the ethanol group. Together, these results indicate that GM-CSF treatment has previously unrecognized effects in promoting alveolar epithelial barrier integrity and that these salutary effects may be particularly relevant in the setting of chronic alcohol abuse.  相似文献   

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20.
Despite more than a 10-fold increase in T cell numbers in G-CSF-mobilized peripheral blood stem cell (PBSC) grafts, incidence and severity of acute graft-vs-host disease (GVHD) are comparable to bone marrow transplantation. As CD1d-restricted, Valpha24+Vbeta11+ NKT cells have pivotal immune regulatory functions and may influence GVHD, we aimed to determine whether G-CSF has any effects on human NKT cells. In this study, we examined the frequency and absolute numbers of peripheral blood NKT cells in healthy stem cell donors (n = 8) before and following G-CSF (filgrastim) treatment. Effects of in vivo and in vitro G-CSF on NKT cell cytokine expression profiles and on responsiveness of NKT cell subpopulations to specific stimulation by alpha-galactosylceramide (alpha-GalCer) were assessed. Contrary to the effects on conventional T cells, the absolute number of peripheral blood NKT cells was unaffected by G-CSF administration. Furthermore, responsiveness of NKT cells to alpha-GalCer stimulation was significantly decreased (p < 0.05) following exposure to G-CSF in vivo. This hyporesponsiveness was predominantly due to a direct effect on NKT cells, with a lesser contribution from G-CSF-mediated changes in APC. G-CSF administration resulted in polarization of NKT cells toward a Th2, IL-4-secreting phenotype following alpha-GalCer stimulation and preferential expansion of the CD4+ NKT cell subset. We conclude that G-CSF has previously unrecognized differential effects in vivo on NKT cells and conventional MHC-restricted T cells, and effects on NKT cells may contribute to the lower than expected incidence of GVHD following allogeneic peripheral blood stem cell transplantation.  相似文献   

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