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

Due to its similar biological activities to interleukin 10 (IL-10), Epstein-Barr virus (EBV) BCRF1 gene product (viral IL-10: vIL-10) has recently been recognized as an analogue of authentic IL-10. Preincubation of human monocytes with vIL-10, like human IL-10, induced smaller amounts of interferon-gamma (IFN-gamma) mRNA in activated human peripheral blood mononuclear cells (PBMNCs) than nonpreincubation, indicating that vIL-10 acts principally on monocytes. Since the activation of monocytes and their generation of oxidative products are regulated by various cytokines, we examined the effects of vIL-10 on superoxide anion (O2-) production by human PBMNCs and monocytes. Not only PBMNCs but also monocytes preincubated with vIL-10 showed a smaller production of O2-. Inhibition was achieved in a dose-dependent fashion and increased gradually after incubation with vIL-10. Additions of IFN-gamma, macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), which prime monocyte activation and induce O2- production, were also affected by the reciprocal effect of vIL-10. Thus, vIL-10 production by EBV-infected cells may be involved in the development of EBV-related disorders.
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PMID:Epstein-Barr virus BCRF1 gene product (viral interleukin 10) inhibits superoxide anion production by human monocytes. 133 11

Chronically immunosuppressed individuals are susceptible to lymphoreticular tumors. Up to 15% of patients with congenital deficiencies such as ataxia=telangiectasia may develop malignancies, mainly high-grade B cell non=Hodgkin's lymphomas (NHLs). AIDS lymphomas are comprised of NHLs including Burkitt's lymphoma (BL) and primary cerebral lymphomas (PCLs). Almost 3% of all AIDS patients (2824 of 97,258 cases) developed NHL. Epstein-Barr virus (EBV) as a co-factor in AIDS lymphomagenesis has been studied: in 12 cases of 24 AIDS lymphomas EBV by DNA in situ hybridization was found. In an analysis of 6 primary cerebral lymphomas, .5 were positive for EBV DNA by Southern blotting. In Burkitt's lymphoma the characteristic genetic alteration affects the c-myc oncogene. In 1/3 of BL p53 mutations were found but none in the 43 NHLs suggesting that p53 mutations and c-myc activation act synergistically in the pathogenesis of these tumors. Cytotoxic agents dideoxyinosine, dideoxycytosine, and zidovudine may cause secondary neoplasia. 8 of 55 AIDS patients under zidovudine treatment developed high-grade lymphoma 23.8 months subsequently; recently doses were reduced. PCL was found in 21 of 90 patients. A 5.2 months survival was associated with combined treatment with cyclophosphamide, Oncovin (vincristine), methotrexate, etoposide, and cytosine arabinoside compared with 11.3 months with chemotherapy. Colony-stimulating factors (CSFs) alleviate drug-induced myelotoxicity and zidovudine-induced neutropenia, however, l8 of 11 patients receiving granulocyte-macrophage CSF developed hematological toxicity. Interleukine-2 produced by T-helper cells enhancing tumor cells cytotoxicity has been used in AIDS-associated cryptosporidial diarrhea and in 4 patients with AIDS lymphoma with modest response, but its stimulation of the HIV-infected substrate may increase viral proliferation.
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PMID:AIDS lymphomas. 161 63

The expression "immunocompromised host" refers to an individual who has one or more defects in the body's natural defense, which leads to severe, often life-threatening, infections. Alcoholism, diabetes mellitus, advanced age, the use of antacids, and viral infections have immune-modulating effects. The human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, and Non A, Non B hepatitis virus also contribute to immunosuppression. The lung has a special vulnerability to infection, and pneumonia accounts for more than 40% of deaths in the immunosuppressed population. Diagnostic methods include detection of microbial antigens by monoclonal antibodies, DNA sequences by the polymerase chain-reactions or DNA probes, and unique metabolites of pathogens by gas chromatography. Transtracheal aspiration was used to obtain uncontaminated respiratory secretions, but fiberoptic bronchoscopy with shielded brush and bronchoalveolar lavage (BAL) is a better means of diagnosis because of a 90% sensitivity in diagnosing pneumocystis infection. Percutaneous aspiration and open lung biopsy are reserved for more complicated cases. Empiric treatment is justified in far advanced AIDS or relapsed myelogenous leukemia with limited life expectancy, or when there is uncontrollable bleeding diathesis or impaired pulmonary function as invasion diagnostic procedures will not be tolerated. The most important antiinfective measure is careful hand washing, while prophylactic antibiotics, selective decontamination, and antifungal, antiviral, and antiparasitic agents can be used. Active and passive immunization against specific pathogens, immunological reconstitution with granulocyte-macrophage colony-stimulating factor (GM-CSF) and reducing the dosage of immunosuppression are the other strategies for prevention. In the last several decades there has been substantial progress in the management of chronic diseases which used to be fatal.
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PMID:Pulmonary infections in the immunocompromised host. 166 54

Cytotoxic T-lymphocytes (CTLs) specific for autologous human squamous cell cancer of the lung were generated by stimulation of peripheral blood lymphocytes with autologous tumor cells in vitro. The CTL line was >97% CD3+, CD8+, CD16- and produced tumor necrosis factor-alpha, gamma-interferon, and granulocyte-macrophage colony-stimulating factor after stimulation with autologous tumor. The CTLs lysed autologous tumor but failed to recognize autologous or histocompatibility leukocyte antigen-matched lymphoid cells, K562, or allogeneic tumor cells of several histological types. Antibody-blocking studies suggested that the CTLs recognized one or more antigens presented by the class I major histocompatibility complex molecule Aw68. To characterize these antigens further, histocompatibility leukocyte antigen Aw68 molecules were extracted from the squamous cell cancer of the lung tumor line by immunoaffinity chromatography, and the associated peptides were eluted in acid and separated by reversed-phase high-performance liquid chromatography. Reconstitution of the CTL epitope was evaluated by adding these peptides to autologous Epstein-Barr virus-transformed B-cells. Two peaks of reconstituting activity were observed, suggesting that these CTLs recognize at least two Aw68-associated peptides. This study confirms the existence of a CTL response against autologous human squamous cell cancer of the lung and suggests that this CTL response is directed against peptide epitopes presented by the class I major histocompatibility complex molecules. It is anticipated that this approach will permit identification of peptide epitopes for lung cancer-specific CTLs.
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PMID:Cytotoxic T-lymphocyte response to autologous human squamous cell cancer of the lung: epitope reconstitution with peptides extracted from HLA-Aw68. 751 55

Interleukin-2 (IL-2)-dependent large granular lymphocytes (LGL) with a distinctive surface phenotype were generated from histologically normal duodenal biopsy tissues. Immunoperoxidase staining of the mucosa with an anti-CD56 monoclonal antibody revealed LGL localized in the lamina propria rather than in the epithelium. Light and electron microscopy demonstrated azurophilic and electron-dense cytoplasmic granules. Flow cytometry analysis revealed that these cells express CD45, CD56, CD2, CD7, CD11a, CD18, CD69 and the intermediate affinity (p70) IL-2 receptor (IL-2R) but not CD57, CD16, CD3, CD4, CD5, CD8, CD45RA, CD25, or the high affinity p55 IL-2R. The LGL proliferated when cultured in the presence of human rIL-2 but not in the presence of human rIL-4. Functional studies demonstrated that the LGL had strong cytotoxicity against natural killer (NK) target cells, K562, but not NK-resistant targets such as Colo 205, Melanoma and Epstein-Barr virus (EBV)-transformed B-cell lines. The LGL expressed genes for IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha) and the corresponding cytokines were detected in culture supernatant. These results provide evidence for an important role of gut mucosal LGL in the induction and regulation of inflammation and immunity in the gut.
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PMID:Morphological, phenotypic and functional characteristics of a pure population of CD56+ CD16- CD3- large granular lymphocytes generated from human duodenal mucosa. 769 28

To obtain a better understanding of the immune response to Epstein-Barr virus (EBV), we measured the cytokines tumour necrosis factor (TNF)-alpha/beta, interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the conditioned medium of peripheral blood mononuclear cells from 10 healthy adults before and at 48 h and at 1, 2, 3 and 4 weeks following infection in vitro with EBV. Cultures were examined for regression of outgrowths of nascent virus-transformed B cells, and populations of cells in the cultures were analysed by flow cytometry. TNF-alpha/beta was not detected in infected or non-infected cultures. In infected cultures assayed at the nominated times, the highest levels of IL-2 were detected at 48 hours, IFN-gamma at 1 week, IL-6 at 2 weeks and GM-CSF between 2 and 4 weeks. IL-6 and GM-CSF, but not IL-2 or IFN-gamma, were detected in non-infected cultures but at lower levels than in infected cultures. Nine of the 10 healthy adults showed regression of outgrowths of virus-transformed B cells and, of these, seven had antibodies to the EBV capsid antigen (VCA). Strong regression was associated with sequential increases in IL-2, IFN-gamma, and low levels of IL-6 and GM-CSF. Absent or weak regression was associated with an undetectable level of IL-2, a low level of IFN-gamma, high levels of IL-6 and GM-CSF and an increased frequency of cells bearing the phenotype CD20 and HLA-DR in the final weeks of culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine production in response to Epstein-Barr virus infection of peripheral blood mononuclear cells in vitro. 822 95

We have established dendritic cell (DC) cultures from chimpanzee peripheral blood mononuclear cells (PBMC) by using recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) and rh interleukin-4 (IL-4) and demonstrate that these cells have all the characteristics of DC as described for other species. We consistently can obtain 1 x 10(7) DC per 100 ml of blood, a yield of 5% DC as compared to 0.1 to 0.5% DC reported in fresh human PBMC. The cultured DC have a varied morphology with typical cytoplasmic extensions. Phenotypically, the blood-derived DC lack expression of most lineage antigens, but express CD83, an antigen specifically expressed on human blood DC. Chimpanzee DC express very high levels of major histocompatability complex class II antigens, adhesion and costimulatory molecules. Consistent with this phenotype of a powerful antigen-presenting cell, chimpanzee DC generate allogeneic mixed leukocyte responses 15 to 20 times more potent than that elicited by macrophages, Epstein-Barr virus-transformed lymphoblasts and fresh PBMC. In addition, chimpanzee DC very efficiently present tetanus toxoid to PBMC-derived CD4+ T cells as compared to macrophages and PBMC. The DC generated by culturing chimpanzee PBMC with rhGM-CSF and rhIL-4 thus closely resemble human blood-derived DC propagated in the same manner. This technology provides a powerful animal model with which to apply DC to clinical studies with relevance to human disease. In particular, chimpanzee DC can be tested as immunotherapeutic agents for cancer, and be studied in relation to the pathogenesis of human immunodeficiency virus (HIV) infection.
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PMID:Chimpanzee dendritic cells with potent immunostimulatory function can be propagated from peripheral blood. 867 5

Neutrophils play an important role in the control of viral infections by releasing a variety of potent agents. We previously demonstrated that Epstein-Barr virus (EBV) binds to human neutrophils and stimulates cytokine synthesis including interleukin-1 (IL-1) and IL-1 receptor antagonist (IL-1Ra). Since neutrophil functions are known to be modulated by the priming effect of granulocyte-macrophage colony-stimulating factor (GM-CSF), we therefore investigated the cellular source of GM-CSF synthesis following treatment of leukocytes with EBV and the effect of GM-CSF on the production of IL-1, IL-1Ra, and superoxide by EBV-treated neutrophils. In enriched-cell populations, only monocytes were found to produce GM-CSF in response to EBV, which was maximal after 12 h of incubation. The results obtained with UV-irradiated particles or EBV neutralized with monoclonal antibody 72A1 suggest that contact between the cell and the gp350 of the viral envelope is sufficient to induce the release of GM-CSF. On the other hand, GM-CSF differentially upregulated EBV-induced IL-1 and IL-1Ra production by neutrophils. Pretreatment of neutrophils with GM-CSF prior to EBV activation synergistically enhanced the production of IL-1 alpha and IL-1 beta, but only marginally affected IL-1Ra synthesis. In addition, GM-CSF was also found to synergistically enhance the superoxide production by neutrophils in response to EBV. Molecular analysis showed that GM-CSF did not alter the IL-1 beta and IL-1Ra mRNA synthesis induced by EBV, suggesting that GM-CSF could act at a posttranslational level. Local production of GM-CSF by monocytes in tissues invaded by EBV could serve to potentiate the host defense mechanisms directed toward the destruction of the infectious virus.
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PMID:Epstein-Barr virus induces GM-CSF synthesis by monocytes: effect on EBV-induced IL-1 and IL-1 receptor antagonist production in neutrophils. 940 Jun 7

Epstein-Barr virus (EBV) transformed human B cells proliferate indefinitely in vitro, and it has been proposed that cytokine-mediated autocrine loops contribute to the maintenance of the lymphoblastoid phenotype. We used a novel multiprobe RNase protection assay to quantify cytokine mRNA species expressed by EBV-transformed lymphoblastoid cell lines (LCL), derived either by the transformation of B cells with B95-8 or wild-type EBV or by the in vitro outgrowth of EBV-associated B cell lymphomas to identify cytokines that are commonly expressed in all LCL and thus more likely to be essential for immortalization of B cells. All 16 LCL expressed high levels of tumor necrosis factor (TNF)alpha, TNFbeta, and transforming growth factor (TGF)beta1 mRNA, while interleukin (IL)-10 transcripts were detected in most LCL but at a lower level. Expression of IL-1alpha, IL-1beta, IL-6, IL-12p35, IL-12p40, IL-13 and IFNgamma mRNA was variable among the LCL tested. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, IL-4, and IL-5 mRNA were undetectable in all LCL. Furthermore, we found that IL-10, TNFalpha, and TNFbeta mRNA were induced in EBV-negative B cell lines after infection with EBV. These data define common versus idiosyncratic patterns of cytokine expression by LCL and, in the former case, such cytokines as TNFalpha, TNFbeta, and IL-10 emerge as strong candidates that are essential for the autocrine regulation of EBV-immortalized B cells.
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PMID:Common and idiosyncratic patterns of cytokine gene expression by Epstein-Barr virus transformed human B cell lines. 947 49

The role of neutrophils during Epstein-Barr virus (EBV) infection is not known. Disruption of the initial and nonspecific immune response may favor the spread of EBV infection. We have previously shown that EBV interacts with human neutrophils and modulates protein expression. In this study we have investigated the ability of EBV to infect neutrophils. Electron microscopy studies showed penetration of virus and its subsequent localization to the nucleus. The presence of viral genomes in isolated nuclei from neutrophils was also shown by polymerase chain reaction (PCR). Expression of viral transcripts like EBNA-2 (Epstein-Barr nuclear antigen-2) and ZEBRA (BamHI Z EBV replication activator) was not detected by reverse transcriptase (RT)-PCR, suggesting that EBV does not seem to establish a latent or a lytic infection in neutrophils. However, at 20 hours post-EBV infection, 77% of cells were apoptotic as compared to 22% in uninfected cell cultures, as evaluated by flow cytometry. This EBV-induced apoptosis was prevented by the addition of granulocyte-macrophage colony-stimulating factor to the cell cultures. Apoptotic cell death seems to implicate the Fas/Fas ligand (L) pathway, as reflected by an increase of Fas/Fas L expression on neutrophils treated with EBV and an increase of soluble Fas L, which may function in an autocrine/paracrine pathway to mediate cell death. Lastly, EBV genome was detected from neutrophils of infectious mononucleosis (IM) patients in contrast to neutrophils obtained from healthy EBV-seropositive donors. Our findings on the interactions of EBV with neutrophils will then provide new insights on the immunosuppressive effects associated with EBV infection.
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PMID:Epstein-Barr virus infects and induces apoptosis in human neutrophils. 963 29


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