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)

I-A+ epidermal antigen-presenting cells (APCs, Langerhans cells) have been shown to present tumor-associated antigens (TAAs) and to induce tumor immunity in vivo. This study examined the effects of ultraviolet radiation (UVR) and the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha) on the ability of epidermal cells (ECs) to induce or to elicit immunity against the murine spindle cell tumor S1509a. Naive syngeneic mice were immunized three times at weekly intervals with ECs that had been cultured in GM-CSF for 18 h and then pulsed with TAA derived from S1509a. This resulted in protective immunity against subsequent tumor challenge, providing a model to study the conditions required for sensitization against TAAs by epidermal APCs. Culture of ECs in GM-CSF was required for induction of significant protective tumor immunity, and UV irradiation or incubation in TNF-alpha for 2 h after GM-CSF incubation abrogated the immunostimulatory effect of GM-CSF. However, unlike UVR, TNF-alpha did not significantly inhibit the induction of immunity when ECs were exposed to TNF-alpha before overnight incubation in GM-CSF, together with GM-CSF, or after pulsing with TAA, and anti-TNF-alpha antibody treatment did not abrogate the effects of UVR on this system. Furthermore, TNF-alpha incubation of ECs augmented their ability to elicit delayed-type hypersensitivity (DTH) and also enhanced elicitation of DTH by GM-CSF-cultured ECs, whereas UV-irradiation reduced it in a dose-dependent fashion. Taken together, these results demonstrate that GM-CSF, TNF-alpha, and UVR are significant regulators of tumor antigen presentation by epidermal APCs and that the effects of the cytokines examined differ with regard to induction or elicitation of immunity.
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PMID:Tumor antigen presentation by epidermal antigen-presenting cells in the mouse: modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and ultraviolet radiation. 150 78

Leukocytosis in association with malignancy has been well described, but the cause is not known. One potential explanation is production of a colony-stimulating factor by the tumor, and this has been demonstrated in vitro. The authors report two patients with lung cancer, leukocytosis, and eosinophilia. The pleural fluid of both patients contained malignant cells and biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF), as demonstrated by radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and colony-forming unit-granulocyte-macrophage (CFU-GM) assay. To determine whether GM-CSF is normally detectable in pleural fluid, the authors performed assays on an additional 11 patients with pleural effusions of various origins but without peripheral blood leukocytosis and eosinophilia; only 1 patient had a detectable level of GM-CSF (i.e., greater than or equal to 0.1 ng/ml). Because GM-CSF usually is not present in pleural fluid, the authors postulate that the high levels of GM-CSF found in the pleural fluid of these two patients was produced by their tumors, and production of GM-CSF by their lung cancers likely caused the leukocytosis with eosinophilia.
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PMID:Production of granulocyte-macrophage colony-stimulating factor in two patients with lung cancer, leukocytosis, and eosinophilia. 154 Aug 71

Interleukin-6 (IL-6) has been shown to inhibit growth and induce differentiation of several myeloid leukemia cell lines. In this work, two in vivo models of acute myeloid leukemia (AML) in mice have been used to test the therapeutic potential of recombinant human IL-6. In mice inoculated by a transplantable AML tumor, IL-6 injections inhibited the development of leukemia and increased survival. The effect was related to dose and length of treatment. In a model of radiation-induced leukemogenesis in SJL/J mice, administration of low-dose IL-6 for 10 days, 4 months after irradiation, reduced the incidence of leukemia observed during 1 year, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the incidence of leukemia. In vitro liquid cultures of leukemic blood cells obtained from AML patients showed that IL-6 slowed growth and decreased the proportion of blasts with an increase in more mature myeloid elements in 72% of M1, M2, M4 AML cases. In contrast, GM-CSF less often produced differentiation but stimulated leukemic cell growth in liquid cultures, without synergism by IL-6.
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PMID:Antitumor effects of human recombinant interleukin-6 on acute myeloid leukemia in mice and in cell cultures. 157 51

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

Most studies of antibody-dependent cellular cytotoxicity (ADCC) by polymorphonuclear leukocytes (PMN) have supported oxidative lytic processes. This may be because the studies used nonhuman or nonneoplastic cells that were highly sensitive to reactive oxygen species or were small enough to be phagocytosed by PMN. We therefore investigated whether oxygen radicals participate in PMN cytotoxicity toward human neuroectodermal solid tumor cells sensitized by 3F8, which is an anti-ganglioside GD2 murine IgG3 monoclonal antibody with documented anticancer activity in humans. A 4-h 51Cr release assay was used to assess tumor cell lysis by hydrogen peroxide, superoxide, and hypochlorite. Nine of 11 GD2(+) human melanoma and neuroblastoma cell lines had equal or greater resistance to these oxidants as compared to a GD2(-) human carcinoma line (SKBr1-III) found by others (and confirmed by us) to be significantly more resistant to oxidative lysis than a murine cell line (P388D1) representative of those commonly used in cytotoxicity assays. To facilitate detection of oxidant-mediated lysis, subsequent studies of 3F8-mediated ADCC used GD2(+) targets that were relatively sensitive and others that were relatively resistant to oxygen radicals. Normal PMN and PMN obtained from children with chronic granulomatous disease, which do not generate reactive oxygen species, were equally effective in ADCC. Granulocyte-macrophage colony-stimulating factor, which primes oxidative responses of normal but not of chronic granulomatous disease PMN, enhanced ADCC by both kinds of PMN. During ADCC of 3F8-sensitized targets, with or without granulocyte-macrophage colony-stimulating factor, GD2(-) "innocent bystander" tumor cells (including P388D1) were not lysed, a finding consistent with unimportant extracellular release of cytotoxic mediators. Finally, antioxidant and antimyeloperoxidase moieties did not block ADCC. We conclude that oxidants are not key factors in 3F8-mediated lysis by PMN of human neuroectodermal tumor cells.
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PMID:Clinically effective monoclonal antibody 3F8 mediates nonoxidative lysis of human neuroectodermal tumor cells by polymorphonuclear leukocytes. 165 2

Granulocyte (G)-CSF and granulocyte-macrophage (GM)-CSF enhance phagocyte survival and function and are produced by fibroblasts and endothelial cells after induction by inflammatory mediators such as IL-1. Our ability to detect G-CSF and GM-CSF activity in the conditioned medium of the human astroglial tumor cell line, U87MG, and molecularly clone the cDNA for G-CSF from a U87MG cDNA library raised the possibility that astroglial cells are capable of G-CSF and GM-CSF production within the central nervous system; if so, the production of these CSF by astroglial cells may be inducible by IL-1. We examined the effects of IL-1 alpha and IL-1 beta on the production of G-CSF and GM-CSF by U87MG and U373MG, another astroglial tumor cell line that does not constitutively produce CSF. We demonstrate that both U87MG and U373MG can be induced to produce G-CSF and GM-CSF by exposure to IL-1 alpha and IL-1 beta. This response, measured by accumulation of increased CSF mRNA, is rapid, sensitive and due to the enhanced stability of CSF message following IL-1 exposure. The implications of these findings to the immunopathogenesis of central nervous system infections are discussed.
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PMID:Monokine modulation of human astroglial cell production of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. I. Effects of IL-1 alpha and IL-beta. 169 Feb 40

In order to obtain more insight into the nature of the abnormal in vitro colony formation in myelodysplastic syndromes (MDS), we investigated the kinetics of the colony formation of 23 MDS cases in response to recombinant human interleukin-3 (IL-3), Granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating Factor (G-CSF), and giant cell tumor cell line conditioned medium (GCT-CM). The kinetics of GCT-CM-induced colony formation were comparable to that of G-CSF-induced colony growth, both in MDS and in normal bone marrow cultures. Colony formation was found to be delayed in MDS. The delay in colony formation was most apparent in the GCT-CM (G-CSF) responsive progenitor cell compartment. In MDS cases with clinical features of high risk disease, this delay was more pronounced as compared with low risk cases (7 and 3 days, respectively, in response to GCT-CM). The delay in colony formation was found to be caused by an increase in the time interval before progenitor cells had begun to divide. These results suggest that a prolongation of the time spent in G0 of myeloid progenitor cells in MDS may be the cause of the indolent in vitro colony formation observed in this disease.
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PMID:The effects of interleukin-3, GM-CSF, and G-CSF on the growth kinetics of colony-forming cells in myelodysplastic syndromes. 169 40

The immune response at the molecular level is characterized by a carefully coordinated interplay of both cytokine production and receptor induction. The regulation of these molecules including the closely related tumor necrosis factors alpha (TNF) and beta (lymphotoxin, LT) is still incompletely understood. We have examined the effects of various cytokines on the expression of TNF and LT mRNA in human peripheral blood mononuclear cells (PBMC). Northern blot analysis with total cellular RNA from mixed populations of PBMC revealed that genes coding for TNF and LT were not spontaneously expressed. Treatment of PBMC with recombinant interleukin (IL)-2 resulted in a high level expression of TNF and LT mRNA. Whereas IL-1 beta was equally effective as IL-2 in inducing both TNF and LT mRNA, granulocyte-macrophage colony-stimulating factor selectively induced only TNF mRNA. Both TNF and LT mRNA were minimally induced by IL-1 alpha, IL-3, interferon (IFN)-alpha, or IFN-gamma. Similarly TNF alone had little effect on induction of TNF and LT mRNA. In conjunction with IL-2, cytokines such as IFN-alpha, IFN-gamma, or TNF did not interfere with IL-2 induction of TNF and LT mRNA. Interestingly, IL-4 in combination with IL-2 inhibited the IL-2-driven induction of TNF and LT mRNA. This inhibitory effect of IL-4 was also observed at the level of TNF and LT protein secretion. Furthermore, IL-4 was also inhibitory of IL-2-mediated induction of Tac mRNA in PBMC. These results extend the interrelationship of cytokine regulation of TNF and LT expression. In particular, they reveal the previously unrecognized function of IL-4 in antagonizing the IL-2 induction of TNF, LT, and Tac mRNA in PBMC.
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PMID:Cytokine regulation of tumor necrosis factor-alpha and -beta (lymphotoxin)-messenger RNA expression in human peripheral blood mononuclear cells. 169 66

The expression of granulocyte colony-stimulating factor (G-CSF) mRNA was studied in human non-hematopoietic tumors, including 18 cases of lung cancers 10 cases of stomach cancers, three cases of glioblastomas, and one case each of breast phyllode sarcoma, thyroid cancer, and hepatocellular carcinoma. Northern blot analysis detected G-CSF mRNA in two of the lung cancer cases, in one of the glioblastoma cases, and in both the breast phyllode sarcoma and hepatocellular carcinoma cases. Since G-CSF receptors were not detected on the tumor cells by 125I-G-CSF binding assay, G-CSF autocrine loop are probably not involved in the growth of these G-CSF-producing tumors. Interestingly, granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA was concomitantly expressed in most of these G-CSF-producing tumors. No major gene deletions or rearrangements of G-CSF and GM-CSF genes were demonstrated by Southern blot analysis in the tumors expressing G-CSF and GM-CSF mRNAs except for one of the glioblastomas (G3) in which one chromosome 17 allele was deleted. Although the mechanism of the concomitant expression of G-CSF and GM-CSF mRNA is unknown, relatively high frequency of this phenomenon suggests the presence of common transcriptional factors acting on regulatory regions of G-CSF and GM-CSF genomes.
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PMID:Expression of granulocyte and granulocyte-macrophage colony-stimulating factors by human non-hematopoietic tumor cells. 170 53

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.
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PMID:Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level. 170 62


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