Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 2 (IL-2) administration is known to induce marked eosinophilia. To evaluate the potential role of eosinophils as anti-tumor effectors and to understand the direct or indirect effects of IL-2 on eosinophils, the physical and functional characteristics of eosinophils obtained during IL-2 therapy were compared with those of eosinophils obtained from the same patients before IL-2 administration, or from healthy donors. The treatment schedule consisted of subcutaneous (s.c.) injections of IL-2, and was performed in 7 patients with small-cell lung cancer (SCLC) in advanced stage. A marked increase of hypodense cells in peripheral blood was found to correlate with eosinophil activation in patients undergoing IL-2 therapy. Cytotoxic activity of eosinophils against allogeneic tumor cells (SCLC, K562 and melanoma lines), as assessed by direct and antibody (Ab)-dependent cellular cytotoxicity (ADCC), was markedly increased during IL-2 therapy. Conversely, eosinophils obtained before treatment, like those of healthy donors, lacked any activity against tumor cells. Sera from IL-2-treated, but not from untreated, patients, significantly improved the in vitro survival and anti-tumor cytotoxicity of eosinophils from healthy donors. Comparable effects were obtained with eosinophils cultured with interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF) and, to a lesser extent, by tumor necrosis factor-alpha (TNF alpha), while no direct activity was mediated by IL-2. A 91% inhibition of eosinophil ADCC was found after pre-incubation of the sera of IL-2-treated patients with anti-IL-5 but not with anti-GM-CSF or anti-TNF alpha Ab. IL-5 mRNA expression was detected in peripheral-blood lymphocytes (PBL) obtained 4 hr after IL-2 injection during the second and third week of IL-2 therapy. Phenotypic analysis of eosinophils from IL-2-treated patients showed enhanced expression of activation markers, including Fc gamma RII (CD32), HLA-DR, CR3 (CD11b) and CRI (CD35). These findings suggest that a significant cytotoxicity against tumor cells can be mediated by eosinophils after indirect, IL-5-mediated in vivo activation by IL-2, and that eosinophils may be involved in the anti-tumor response(s) induced in vivo by IL-2.
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PMID:In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5. 838 11

Eosinophils are important in antibody-mediated immune defense against parasites based on interaction with Ig receptors (FcR). Of the three classes of IgG FcR in humans, hFc gamma RI, II, and III, solely hFc gamma RII (CD32) is expressed on freshly isolated eosinophils. Despite an expression level similar to that found on monocytes and polymorphonuclear granulocytes, binding activity of hFc gamma RII on eosinophils is constitutively low. Freshly isolated eosinophils had a negligible ability to form rosettes with IgG-sensitized erythrocytes (EA-IgG). Addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) caused an approximately threefold increase in EA-IgG rosettes. This increase was maximal after 35 minutes, and declined upon further incubation at 37 degrees C. Analysis of hFc gamma RII expression levels showed no significant changes and neither was the expression of other hFc gamma R classes induced. Blocking studies with anti-Fc gamma receptor monoclonal antibody (MoAb) proved hFc gamma RII specificity of enhanced IgG complex binding. These phenomena were not restricted to GM-CSF action, because the addition of interleukin-3 or interleukin-5 similarly enhanced EA-IgG binding. The kinetics of activation of hFc gamma RII binding activity were paralleled by the binding of EA-C3bi to CR3 on eosinophils. In contrast to the stable expression of hFc gamma RII during activation with GM-CSF, CR3 expression increased slowly. Ligand binding via both types of opsonin receptors proved receptor specific. However, the kinetics of enhanced binding via hFc gamma RII and CR3 suggested the possibility of a common mechanism underlying the enhancement of ligand binding via hFc gamma RII and CR3. This hypothesis was supported by the fact that binding via hFc gamma RII proved sensitive to both high concentrations of F(ab')2 fragments of anti-CD11b MoAb MO1 and chelation of bivalent cations with EDTA. In conclusion, our studies indicate that cytokines can induce a transient enhancement of hFc gamma RII binding activity. Qualitative, and not quantitative, changes in this receptor appear to underly the modulation of binding activity, which may be linked to changes in CR3 activity.
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PMID:Granulocyte-macrophage colony-stimulating factor induces sequential activation and deactivation of binding via a low-affinity IgG Fc receptor, hFc gamma RII, on human eosinophils. 848 20

Peripheral blood (PB) eosinophils rapidly undergo apoptosis and cell death in vitro unless cultured in the presence of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) in which their survival is prolonged for up to 10 days. CD69 is a type II membrane antigen expressed by cytokine-activated, but not freshly isolated, PB human eosinophils. We have examined the effect of ligation of CD69 by specific monoclonal antibody (MoAb) on the viability of human eosinophils cultured with recombinant human (rh)GM-CSF. Eosinophils were purified by immunomagnetic selection and cultured with GM-CSF (10(-10) mol/L). Eighteen hours after the start of culture, a panel of CD69 MoAb or controls (anti-CR3 or isotype-matched control MoAb) were added. Viability was assessed by trypan blue exclusion and apoptosis by morphologic assessment, DNA laddering, and flow cytometric analysis of eosinophil red autofluorescence. Up to 50% of the eosinophils had undergone apoptosis 48 hours after addition of anti-CD69 MoAb compared with less than 10% apoptosis for CR3 or the isotype matched control. The majority of apoptotic eosinophils excluded trypan blue at 48 hours post CD69 ligation. More apoptotic eosinophils were observed at later time-points and this was associated with loss of viability. At 120 hours post-addition of the anti-CD69 MoAb MLR3, 24% +/- 10.6% eosinophils were viable compared with 84% +/- 3.4% for the CR3 control (P < .001). A F(ab)2 fragment of CD69 MoAb P8, also induced apoptosis in GM-CSF cultured eosinophils. A more rapid induction of eosinophil apoptosis was obtained with CD69 MoAb immobilized via their Fc portions on protein-A coated plastic 96 well plates. Ligation of CD69 or CR3 resulted in the release of comparable quantities of eosinophil peroxidase at 48 hours post-ligation. These levels of EPO were consistent with the viability of these cells at 48 hours as assessed by exclusion of trypan blue. Finally, a neutralizing MoAb to TGF beta 1 had no effect on CD69-dependent apoptosis induction nor were there detectable quantities of TGF beta 1 in supernatants from GM-CSF--cultured eosinophils ligated with CD69 or control MoAb. These results suggest that eosinophils cultured with GM-CSF can be induced to undergo apoptosis as a result of cell signalling mediated by perturbation of CD69. This may represent an important physiologic mechanism for eosinophil removal in vivo.
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PMID:Ligation of CD69 induces apoptosis and cell death in human eosinophils cultured with granulocyte-macrophage colony-stimulating factor. 863 99

Colony-stimulating factors are growth factors which induce differentiation of the hematopoietic stem cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates proliferation and improves functions of neutrophils and monocyte/macrophages. A macrophage submesothelial stratum has been suggested to constitute the first line of peritoneal defense. We have tested whether intraperitoneally administered GM-CSF could increase the number and activation of peritoneal macrophages in peritoneal dialysis patients. Eight stable patients injected 17 micrograms of GM-CSF in each of their four daily CAPD bags over three days. The clinical status, the peritoneal effluent and peripheral blood cell count, membrane receptor expression, phagocytosis activity and cytokine levels were monitored at days 0, 1, 3, 10 and 28. GM-CSF administration caused a large increase in peritoneal macrophage number (89-fold mean increase after 72 hr), returning to baseline seven days after withdrawal. GM-CSF triggered an increase in the expression of CD11b/CD18 (CR3) and its counterreceptor CD54, indicating the cellular progression into a more activated state. Both the number of phagocytic cells (55 +/- 15% to 83 +/- 10%, P < 0.05) and the phagocytic index (137 +/- 29 to 255 +/- 61, P < 0.01) were also augmented. Peritoneal effluent cytokine-chemokine levels demonstrated an increase in IL-6 and MCP-1 levels while TNF-alpha, IL-1, IL-8, MIP-1 alpha and RANTES were not significantly altered. GM-CSF administration did not affect the peritoneal transport of water or solutes. Minor side-effects were registered in two patients. In conclusion, intraperitoneal GM-CSF causes a marked and transient recruitment of primed macrophages into the peritoneum without inducing inflammatory parameters. GM-CSF should improve the peritoneal defensive capacity through potentiation of the effector functions of resident and newly-recruited macrophages.
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PMID:Immunomodulation of peritoneal macrophages by granulocyte-macrophage colony-stimulating factor in humans. 894 92

Treatment of human polymorphonuclear leucocytes (PMNL) separated by density sedimentation (DS) from normal donors (PMNL-NL-DS) with interferon-gamma (IFN-gamma) + granulocyte colony-stimulating factor (G-CSF) lessens the damage caused by isolation and irradiation. We have studied granulocyte-macrophage colony-stimulating factor (GM-CSF) in this system, as well as the behaviour of PMNL collected by continuous flow leucapheresis (CFL) from donors treated with G-CSF (PMNL-GCSF-CFL). After isolation, PMNLs were treated with IFN-gamma + G-CSF, GM-CSF or IFN-gamma + G-CSF + GM-CSF, irradiated with 0 or 30 Gy and studied after 0 and 20 h in cell culture. All regimens reduced apoptosis of PMNL-NL-DS. Killing of Candida albicans by 20-h-old PMNL-NL-DS was best preserved by IFN-gamma + G-CSF treatment. A similar pattern of results was obtained for assays of PMNL-NL-DS chemotaxis and superoxide production. There was a consistent trend toward reduced function after irradiation in all assays. PMNL-GCSF-CFL less often demonstrated the morphological features of apoptosis, and this was further reduced by cytokine regimens containing IFN-gamma + G-CSF. In assays of C. albicans killing and chemotaxis, 20-h-old untreated PMNL-GCSF-CFL performed as well as freshly isolated PMNL-GCSF-CFL. PMNL-GCSF-CFL showed decay in CD11b (CR3), CD16 (Fc gamma III) and CD64 (Fc gamma R1) expression after 20 h in cell culture, but treatment with IFN-gamma + G-CSF preserved expression. There was a trend toward reduced function after radiation. Comparison of PMNL-GCSF separated by CFL and DS demonstrated that CFL itself is a strong inducer of the morphological features of apoptosis. This study shows that while separation by CFL, and irradiation are damaging to PMNLs, damage may be reduced by use of cytokines.
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PMID:Effects of in vitro and in vivo cytokine treatment, leucapheresis and irradiation on the function of human neutrophils: implications for white blood cell transfusion therapy. 914 46


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