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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)

We have examined the regulation of complement dependent phagocytosis by macrophage-activating cytokines. Tumor necrosis factor (TNF)-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not interferon-gamma, interleukin-4 or macrophage-CSF, stimulated ingestion of the encapsulated fungal pathogen Cryptococcus neoformans by resident peritoneal macrophages in vitro. This was dependent upon opsonization of the yeasts with complement, 72 h of incubation with the cytokines for maximum effect, and the obligate involvement of the macrophage CR3 receptor. TNF-alpha and GM-CSF synergized at low concentrations, resulting in dramatic up-regulation of phagocytosis when compared to either cytokine alone. Supernatants from C. neoformans-specific T cells also increased macrophage phagocytic efficiency. Finally, the administration of neutralizing mAb specific for TNF-alpha and GM-CSF increased mortality in C. neoformans-infected mice, and induced the rapid progression of disease with involvement of the brain and meninges. We conclude that TNF-alpha and GM-CSF are potent regulators of complement-dependent phagocytosis by murine macrophages. Macrophage activation with these two cytokines can completely overcome the anti-phagocytic properties of the virulent yeasts. Our results, therefore, implicate TNF-alpha and GM-CSF as important mediators of resistance to encapsulated pathogens such as C. neoformans where ingestion of the organism is a critical process in host resistance.
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PMID:Cytokine enhancement of complement-dependent phagocytosis by macrophages: synergy of tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor for phagocytosis of Cryptococcus neoformans. 160 Oct 35

The abilities of selected cytokines to activate human peripheral blood mononuclear cells (PBMC) to inhibit and kill the opportunistic fungus Cryptococcus neoformans were studied. PBMC were cultured for 7 days in cell wells containing no cytokines, tumor necrosis factor (TNF), gamma interferon (IFN-gamma), 1,25-dihydroxycholecalciferol (vitamin D3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interleukin-2 (IL-2) and were then challenged for 24 h with a fixed number of CFU of C. neoformans. The number of CFU increased in wells containing no cytokines, TNF, IFN-gamma, or vitamin D3 and remained about the same in wells containing GM-CSF. In contrast, the number of CFU in wells containing IL-2-stimulated PBMC decreased, suggesting fungicidal activity. Optimal conditions for IL-2 stimulation included a minimum of 5 days of incubation of PBMC with IL-2, a concentration of 100 U of IL-2 per ml, and a high ratio of effectors to fungi. Separation of IL-2-stimulated PBMC based upon their adherence to plastic revealed that antifungal activity resided in the nonadherent fraction. These data demonstrate that IL-2 and GM-CSF are capable of stimulating PBMC-mediated antifungal activity and suggest that these cytokines may play physiological or pharmacological roles in host defenses against cryptococcosis.
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PMID:Activation of human peripheral blood mononuclear cells by interleukin-2 and granulocyte-macrophage colony-stimulating factor to inhibit Cryptococcus neoformans. 189 53

We have previously reported that continuous intravenous (IV) administration of recombinant granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) to humans following high-dose alkylating agent chemotherapy and autologous bone marrow support (ABMS) results in myeloid bone marrow maturation, accelerated granulocyte recovery, and reduced treatment-related toxicity. However, we found that leukocyte counts declined rapidly after discontinuation of rHuGM-CSF therapy, which suggests possible growth factor effects on leukocyte margination and migration. For these reasons we studied granulocyte margination by using 111In-labeled autologous granulocytes and found similar granulocyte margination before (21.5% +/- 13.4%) and during continuous IV rHuGM-CSF infusion (23.3% +/- 9.6%). Phagocytosis of Cryptococcus neoformans and granulocyte hydrogen peroxide production was similar before and during rHuGM-CSF infusion and similar to patients treated with the same high-dose chemotherapy and ABMS but not receiving growth factor. However, migration of granulocytes to a sterile inflammatory site was markedly reduced during continuous rHuGM-CSF infusion (1.2 +/- 0.9 WBCs/cm2, 24 hr) as compared with baseline (39.6 +/- 17.7 WBCs/cm2/24 hr; P less than .0008). These findings may be of relevance when extravascular granulocytes are required for host defense.
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PMID:Neutrophil migration is defective during recombinant human granulocyte-macrophage colony-stimulating factor infusion after autologous bone marrow transplantation in humans. 304 40

Cryptococcus neoformans is a pathogenic yeast and a major cause of opportunistic infection in AIDS patients. It is commonly found in an acapsular form in the environment, and infection is likely to occur by inhalation. The lung provides a suitable environment for capsule synthesis, and once encapsulated, C. neoformans becomes resistant to phagocytosis. A stable acapsular mutant of the organism is readily ingested by murine macrophages in vitro, indicating entry via constitutively competent receptors. We demonstrate in this report that this process is inhibitable by particles derived from Saccharomyces cerevisiae that are rich in mannan and beta-glucan, as well as more purified forms of these glycans. Furthermore, ingestion of the acapsular form of C. neoformans induces a range of proinflammatory cytokines, including tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor, which, as we have previously shown, enhance ingestion of serum-opsonized encapsulated C. neoformans in vitro. We demonstrate that ingestion of the acapsular form of the organism also enhances ingestion of the pathogenic encapsulated form. This is dependent on the production of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor by the macrophages, since addition of neutralizing antibodies to both cytokines inhibited the observed increase in ingestion. Together, these data demonstrate that ingestion of acapsular C. neoformans is mediated via mannose and beta-glucan receptors on the macrophage surface and that this process activates macrophages for enhanced phagocytosis of the encapsulated form via production of macrophage-derived cytokines.
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PMID:Ingestion of acapsular Cryptococcus neoformans occurs via mannose and beta-glucan receptors, resulting in cytokine production and increased phagocytosis of the encapsulated form. 779 75

The anticryptococcal activity of peripheral blood polymorphonuclear leukocytes (PMN) and monocytes was compared on plastic versus human umbilical vein endothelial cell surfaces. Various amounts of PMN and monocytes were incubated on plastic or endothelial surfaces and then challenged for 18 h with Cryptococcus neoformans. Both phagocyte populations exhibited significantly more anticryptococcal activity on an endothelial cell monolayer than on plastic. Prestimulating the endothelial cell monolayer with interleukin-1 augmented the antifungal activity of PMN but not that of monocytes. In the absence of phagocytes, endothelial cells lacked activity. Blocking antibodies directed against endothelial adhesion molecules ICAM-1 and ELAM-1 did not affect PMN-mediated inhibition of fungal growth. Recombinant interleukin-1 and interleukin-8 (two cytokines secreted by endothelial cells) activated neutrophils for modestly enhanced antifungal activity. However, supernatants derived from endothelial cells, as well as neutralizing antibodies directed against the endothelial cell-derived cytokines interleukin-8 and granulocyte-macrophage colony-stimulating factor failed to augment PMN antifungal activity. PMN viability after 18 h was diminished on plastic compared with endothelial surfaces. While the percentages of C. neoformans bound to neutrophils were similar on both surfaces, the patterns of binding were markedly different: on endothelial (but not plastic) surfaces, most cryptococci were surrounded by greater than five PMN. Thus, phagocyte-mediated inhibition of cryptococcal growth is enhanced on endothelial monolayers compared with plastic surfaces, possibly as a result of differences in phagocyte viability and patterns of binding. Bolstering the activity of circulating phagocytes by stimulating endothelial cells may be of relevance in the treatment of patients with or at risk for cryptococcemia.
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PMID:Effect of endothelial cells on phagocyte-mediated anticryptococcal activity. 835 3

Phagocytosis is a fundamental process in innate resistance to infection. We have used the pathogenic yeast Cryptococcus neoformans to study the interaction of this encapsulated organism with murine macrophages in vitro. In the absence of exogenous opsonins the encapsulated yeast is almost totally resistant to ingestion by murine macrophages. Owing to its ability to activate the alternative complement pathway, the anti-phagocytic properties of the polysaccharide capsule can be partially overcome following opsonization in vitro with non-immune mouse serum and subsequent phagocytosis via complement receptors. Here, we demonstrate the importance of the complement receptor type 3 (CR3) in in vitro phagocytosis of the yeast and in in vivo resistance to infection. In vitro, 70% of a population of resident murine macrophages are able to ingest C. neoformans and then only inefficiently (1-2 organisms per cell). Previously we have shown that tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) efficiently enhance ingestion of serum-opsonized encapsulated C. neoformans, and we now show that the cytokines convert a population of resident macrophages to a state where all the cells are competent for ingestion of large numbers of yeasts (6-8 per cell). We also show that these cytokines have a direct effect on CR3, as enhanced levels of complement-opsonized sheep red blood cells (EIgMC) bind to macrophages activated in this way. However, cytokines that have previously been shown to enhance phagocytosis of EIgMC have no effect on ingestion of encapsulated C. neoformans. These results demonstrate that the cytokines regulating CR3-dependent ingestion of C. neoformans are different to those regulating ingestion of EIgMC and reinforce the importance of studying pathogens rather than inert ligands in understanding the regulation of phagocytosis.
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PMID:CR3-dependent phagocytosis by murine macrophages: different cytokines regulate ingestion of a defined CR3 ligand and complement-opsonized Cryptococcus neoformans. 922 30

In patients undergoing bone marrow transplantation cryptococcosis is rarely encountered. We report a fatal case of Cryptococcus meningitis in a 12-year-old girl with acute lymphoblastic leukemia (ALL) in second remission who had a transplant from a human leukocyte antigen (HLA)-identical unrelated bone marrow donor. The conditioning regimen was thiotepa, cyclophosphamide, and total body irradiation (TBI); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, methotrexate, and antilymphocyte globulin (ALG). The patient experienced stage III GVHD responsive to high-dose corticosteroids. On day +54 a thrombotic microangiopathy occurred. On day +64 neurological status worsened; a brain computed tomographic (CT) scan showed hyperdense lesions suggesting fungal infection. Detection of cryptococcal antigen by latex agglutination was positive but India ink stain and culture were negative. Despite treatment with amphotericin B, 5-flucytosine, and granulocyte-macrophage colony-stimulating factor, the patient died 13 days after the diagnosis.
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PMID:Cryptococcal meningitis following a thrombotic microangiopathy in an unrelated donor bone marrow transplant recipient. 926 80

Human natural killer (NK) cells and T lymphocytes can bind to and inhibit the growth of the yeast-like organism Cryptococcus neoformans. Binding of target cells to NK or T cells also has the potential to modulate cytokine production by the effector cells. In this study, we assessed the ability of C. neoformans to modulate NK cell production, or in some cases T-cell production, of granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumor necrosis factor alpha (TNF-alpha). We found that freshly isolated human NK cells from most individuals make GM-CSF and TNF-alpha constitutively when cultured in vitro. The addition of C. neoformans to T-cell fractions which do not make GM-CSF constitutively did not affect GM-CSF production, but the addition of C. neoformans to NK cell fractions significantly reduced the amounts of GM-CSF produced in most NK cell samples. The reduction in the amount of GM-CSF in C. neoformans-NK cell cocultures could not be attributed to loss of lymphocyte viability or to C. neoformans adsorbing or degrading the cytokine and was dependent on direct contact between the NK cells and cryptococcal cells. GM-CSF was not the only cytokine to be down-regulated. TNF-alpha production was also diminished when NK cells were incubated with C. neoformans. The regulation of both cytokines was at the transcriptional level because GM-CSF and TNF-alpha mRNA levels were lower in NK cell samples incubated with C. neoformans than in NK cell samples incubated without C. neoformans. Diminished production of constitutively produced cytokines resulting from the interaction of NK cells with cryptococcal cells has the potential to affect phagocytic cells in the immediate regional environment and to damp the immune response.
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PMID:Direct interactions of human natural killer cells with Cryptococcus neoformans inhibit granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha production. 935 34

Cryptococcosis is caused by either Cryptococcus neoformans or C. gattii. While cryptococcal meningoencephalitis is caused mostly by C. neoformans in immunocompromised patients, the risk factors remain unclear for patients with no known immune defect. Recently, anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies were detected in the plasma of seven "immunocompetent" cryptococcosis patients, and the cryptococcal strains from these patients were reported as C. neoformans (three strains), C. gattii (one strain), and Cryptococcus (three strains not identified to the species level). We identified all three strains that had not been identified to the species level as C. gattii. Notably, the three strains that were reported as C. neoformans but were unavailable for species confirmation originated from Sothern California and Thailand where C. gattii is endemic. Most clinical laboratories designate C. neoformans without distinguishing between the two species; hence, these three strains could have been C. gattii. Since C. gattii infects more immunocompetent patients than C. neoformans, we pursued the possibility that this antibody may be more prevalent in patients infected with C. gattii than in those infected with C. neoformans. We screened the plasma of 20 healthy controls and 30 "immunocompetent" patients with cryptococcal meningoencephalitis from China and Australia (multiple ethnicities). Anti-GM-CSF autoantibodies were detected only in the plasma of seven patients infected by C. gattii and one healthy volunteer and in none infected by C. neoformans. While plasma from these C. gattii patients completely prevented GM-CSF-induced p-STAT5 in normal human peripheral blood mononuclear cells (PBMCs), plasma from one healthy volunteer positive for anti-GM-CSF autoantibodies caused only partial blockage. Our results suggest that anti-GM-CSF autoantibodies may predispose otherwise immunocompetent individuals to meningoencephalitis caused by C. gattii but not necessarily to that caused by C. neoformans. IMPORTANCE Cryptococcal meningoencephalitis is the most serious central nervous system (CNS) infection caused by Cryptococcus neoformans or C. gattii. Cryptococcus primarily infects immunocopromised patients but is also sporadically encountered in otherwise "immunocompetent" patients with no known risk. In a recent study, anti-GM-CSF autoantibodies were detected in the plasma of seven otherwise immunocompetent patients with cryptococcal meningoencephalitis. Four of seven (57%) cryptococcal isolates from these patients were identified as C. gattii, while three strains were unavailable for species confirmation. We collected plasma from 30 otherwise healthy patients with CNS cryptococcosis in China and Australia (multiethnic) and analyzed the samples for the presence of anti-GM-CSF autoantibodies. The results suggest that anti-GM-CSF autoantibodies are a risk factor for CNS infection by C. gattii but not C. neoformans. GM-CSF may have a specific role in host defense against C. gattii, thereby elevating the importance of determining the level of anti-GM-CSF autoantibodies which can impact clinical management.
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PMID:Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. 2464 64

The two etiologic agents of cryptococcal meningoencephalitis, Cryptococcus neoformans and C. gattii, have been commonly designated as either an opportunistic pathogen for the first species or as a primary pathogen for the second species. Such a distinction has been based on epidemiological findings that the majority of patients presenting meningoencephalitis caused by C. neoformans are immunocompromised while C. gattii infection has been reported more often in immunocompetent patients. A recent report, however, showed that GM-CSF (granulocyte-macrophage colony-stimulating factor) neutralizing antibodies were prevalent in the plasma of "apparently immunocompetent" C. gattii patients with meningoencephalitis. Because GM-CSF is essential for differentiation of monocytes to macrophages and modulating the immune response, it is not surprising that the lack of GM-CSF function predisposes otherwise healthy individuals to infection via inhalation of environmental pathogens such as C. gattii. Since the test for anti-GM-CSF autoantibodies is not included in routine immunological profiling at most hospitals, healthy patients with GM-CSF neutralizing antibodies are usually categorized as immunocompetent. It is likely that a comprehensive immunological evaluation of patients with C. gattii meningoencephalitis, who had been diagnosed as immunocompetent, would reveal a majority of them had hidden immune dysfunction. This paper reviews the relationship between GM-CSF neutralizing antibodies and the risk for C. gattii infection with CNS involvement.
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PMID:Is Cryptococcus gattii a Primary Pathogen? 2937 39


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