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)

M1 myeloid leukemic cells overexpressing wild-type p53 undergo apoptosis. This apoptosis can be suppressed by some cytokines, protease inhibitors, and antioxidants. We now show that induction of apoptosis by overexpressing wild-type p53 is associated with activation of interleukin-1beta-converting enzyme (ICE)-like proteases, resulting in cleavage of poly(ADP- ribose) polymerase and the proenzyme of the ICE-like protease Nedd-2. Activation of these proteases and apoptosis were suppressed by the cytokine interleukin 6 or by a combination of the cytokine interferon gamma and the antioxidant butylated hydroxyanisole, and activation of poly(ADP-ribose) polymerase and apoptosis were suppressed by some protease inhibitors. In a clone of M1 cells that did not express p53, vincristine or doxorubicin induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by interleukin 6. In another myeloid leukemia (7-M12) doxorubicin also induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by granulocyte-macrophage colony-stimulating factor. The results indicate that (i) overexpression of wild-type p53 by itself or treatment with cytotoxic compounds in wild-type p53-expressing or p53-nonexpressing myeloid leukemic cells is associated with activation of ICE-like proteases; (ii) cytokines exert apoptosis-suppressing functions upstream of protease activation; (iii) the cytotoxic compounds induce additional pathways in apoptosis; and (iv) cytokines can also suppress these other components of the apoptotic machinery.
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PMID:Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis. 925 85

Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.
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PMID:Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes. 928 58

In long-term bone marrow cultures we studied the effect of the addition of the myelotoxic agents methotrexate (MTX) and ceftazidime (CEF) on the kinetics of cytokine production in the supernatant (SN) and on mRNA expression in the adherent stromal layer. In response to a medium change, a prompt and significant increase in colony-stimulating activity (CSA) and interleukin 6 (IL-6) concentrations in the SN occurred, peaking 12 h later. Two macrophage colony-stimulating factors (M-CSF) mRNA of 23 kb and 4 kb were identified. In response to the medium change, the 4.0-kb transcript increased significantly six h later. The 2.3-kb transcript expression was stronger than the 4-kb mRNA but did not cycle with medium change. At medium change, IL-6 mRNA was only minimally expressed; then a prompt increase occurred, which peaked six h later. The addition of 500 mg/ml (=915 microM) CEF to the culture caused a dose-dependent suppression of CSA and IL-6 supernatant concentrations and IL-6 and M-CSF mRNA expression. By contrast, 1 microM MTX had minimal effect on cytokine concentrations in the SN following medium change. mRNA expression was, however, suppressed. These results provide insights into the possible mechanisms whereby cytokines lead to increased myeloid cell proliferation following medium change. We also demonstrate that two myelotoxic agents have different effects on cytokine production. This information could be of value in developing rational approaches to the therapeutic use of cytokines in drug-induced neutropenia.
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PMID:Effects of myelotoxic agents on cytokine production in murine long-term bone marrow cultures. 970 48

To evaluate the relationships between serum endogenous cytokine levels and their clinical implications in cancer patients, we measured the serum levels of endogenous granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin 6 (IL-6) in patients with untreated primary lung cancer. The serum G-CSF level was measured using a chemiluminescent ELISA, and the other cytokine levels were measured using ELISA. Fifty healthy adults and 183 patients with primary lung cancer were studied. The mean M-CSF level in the lung cancer patients (1106.4 units/ml) was significantly higher than that in the healthy adults (836 units/ml, P = 0.0001). In patients with large cell carcinoma, endogenous G-CSF, M-CSF, and IL-6 levels were significantly higher than those in patients with carcinomas of other cell types (P < 0.05). Univariate analysis showed that survival of 159 non-small cell lung cancer patients with high (more than cutoff level) G-CSF, M-CSF, and IL-6 levels was significantly poorer than that of patients with low levels (Wilcoxon's test, P = 0.018, P < 0. 0001, and P < 0.0001, respectively). Survival of patients with high levels of two or more cytokines was poorer than that of those with high levels of one cytokine or normal cytokine levels (P < 0.0001). Multivariate analysis using Cox's proportional hazards model showed that high M-CSF and C-reactive protein levels correlated significantly with poor survival (P = 0.037 and 0.037, respectively). Our preliminary data suggest that high M-CSF levels in non-small cell lung cancer may be of poor prognostic value.
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PMID:Serum levels of cytokines in patients with untreated primary lung cancer. 981 3

We demonstrate the constitutive expression of interleukin 6 (IL-6), IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) in normal kidney cells, and in the majority of renal oncocytomas, papillary and non-papillary renal cell carcinomas (RCCs) by reverse transcriptase polymerase chain reaction (RT-PCR) technique. No expression of IL-6 and TGF-alpha and variable expression of GM-CSF, IL-8, EGF and EGFR was seen in chromophobe RCCs. The lack of expression of IL-6 and TGF-alpha might be correlated with the growth pattern, poor vascularity and low malignancy of chromophobe RCCs.
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PMID:Lack of interleukin 6 (IL-6) and transforming growth factor alpha (TGF-alpha) expression in chromophobe renal cell carcinomas. 982 Jan 73

The c-mpl ligand, thrombopoietin (TPO), is a physiologic regulator of platelet and megakaryocytic production, acting synergistically on thrombopoiesis with the growth factors interleukin 11 (IL-11), stem cell factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and granulocyte-macrophage colony-stimulating factor. Because some of these growth factors, especially TPO and IL-11, are now being evaluated clinically to reduce chemotherapy-associated thrombocytopenia in cancer patients, we evaluated 25 acute myeloid leukemia (AML) samples to test whether TPO, IL-11, and other early-acting megakaryocyte growth factors can affect leukemic cell proliferation, cell cycle activation, and programmed cell death (PCD) protection. TPO induced proliferation in the majority of AML samples from an overall mean proportion of S-phase cells of 7.8% +/-1.5% to 14.5% +/- 2.1% (p = 0.0006). Concurrent G0 cell depletion was found in 47.3% of AML samples. TPO-supported leukemic cell precursor (CFU-L) proliferation was reported in 5 of 17 (29.4%) of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. In 13 of 19 samples, a significant protection from PCD (from an overall mean value of 13% +/-0.7% to 8.8% +/- 1.8%;p = 0.05) was detected after TPO exposure. Conversely, IL-11-induced cell cycle changes (recruitment from G0 to S phase) were detected in only 2 of 14 samples (14.2%). In addition, IL-11 showed little, if any, effect on CFU-L growth (mean colony number = 17.5 9.5) or apoptosis. Combination of TPO with IL-11 resulted in only a slight increase in the number of CFU-L, whereas IL-3 and stem cell factor significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 x 10(5) cells plated, respectively. We conclude that TPO induces cell cycle activation in a significant proportion of cases and generally protects the majority of AML blast cells from PCD. On the other hand, IL-11 has little effect on the cell cycle or PCD. Combination of both TPO and IL-11 is rarely synergistic in stimulating AML clonogenic growth. These findings may be useful for designing clinical studies aimed at reducing chemotherapy-associated thrombocytopenia in AML patients.
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PMID:Thrombopoietin and interleukin 11 have different modulatory effects on cell cycle and programmed cell death in primary acute myeloid leukemia cells. 1042 2

We have previously shown that when human umbilical cord blood (UCB) cells are cultured in standard Dexter-type long-term cultures (D-LTC), adherent cells develop forming a discrete net on the bottom of the culture flask. The identity of such cells, however, has not been defined. Accordingly, the major goal of the present study was to characterize the adherent cells developed in standard UCB D-LTC. Cultures were established from 14 UCB samples and from nine bone marrow (BM) samples, as controls. Both UCB and BM cultures were initiated with the same number of mononuclear cells (MNC) (2.5 x 10(6) MNC/ml). After three weeks in culture, adherent cell numbers in UCB D-LTC were 24%-30% of the numbers found in BM cultures. More than 90% of the adherent cells in UCB D-LTC expressed the acid phosphatase enzyme, whereas no alkaline phosphatase-positive cells were observed. This was in contrast to BM D-LTC, in which alkaline and acid phosphatase were expressed by 60%-75% and 20%-45% of the adherent cells, respectively. Immunochemical analysis showed that CD61 (osteoclast marker) and Factor VIII (endothelial cell marker) were not expressed by the adherent cells developed in UCB cultures. Interestingly, the majority of such cells expressed CD1a (dendritic cell marker), CD14, CD68 and CD115 (antigens mainly expressed by macrophagic cells). When the cultures were supplemented with the recombinant cytokines epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor or granulocyte-macrophage colony-stimulating factor (GM-CSF), only GM-CSF had a significant positive effect on adherent cell number. In order to test for some functional properties of the adherent cells developed in culture, production of stem cell factor (SCF), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) was assessed. IL-6 and TNF-alpha showed elevated levels in UCB D-LTC, whereas SCF levels were always below detection. Finally, analysis of fibroblast progenitors (fibroblast colony-forming units [CFU-F]) showed that these cells were present in BM samples (6 CFU-F/10(5) MNC) and were totally absent in UCB samples. Taken together, the results of the present study indicate that the vast majority of the adherent cells developed in standard UCB D-LTC belong to the macrophage lineage and that fibroblasts seem to be absent. Interestingly, the high proportion of CD1a+ cells suggests that dendritic cells are also present in these cultures.
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PMID:Characterization of the adherent cells developed in Dexter-type long-term cultures from human umbilical cord blood. 1066 71

Extensive atrophy has been reported to occur in the thymus in a cancer-burden state but the mechanisms of this atrophy have not been fully elucidated. We investigated changes in the thymus in tumour-bearing mice inoculated with two subclones of the murine colon 26 adenocarcinoma cell line: clone 5 (non-cachectic) and clone 20 (cachectic). In clone 20 mice, body weights and thymocyte numbers decreased significantly compared with controls. Flow cytometric analysis of the thymocytes demonstrated that the frequency of single positive cells (CD4+ CD8- and CD4- CD8+) was significantly increased and that of double positive cells (CD4+ CD8+) was significantly decreased in clone 20 mice and, to a lesser extent, in clone 5 mice compared with controls. Serum levels of interleukin 6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly elevated. These results suggested that thymocyte apoptosis was accelerated in the cancer-cachectic state, and increased GM-CSF might be partly responsible for thymic atrophy.
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PMID:Extensive cell death in thymocytes in colon 26-induced cachectic mice. 1081 46

The interaction of Listeria monocytogenes with endothelial cells represents a crucial step in the pathogenesis of listeriosis. Incubation of human umbilical vein endothelial cells (HUVEC) with wild-type L. monocytogenes (EGD) provoked immediate strong NO synthesis, attributable to listerial presentation of listeriolysin O (LLO), as the NO release was missed upon employment of a deletion mutant for LLO (EGD hly mutant) and was reproduced by purified LLO. Studies of conditions lacking extracellular Ca(2+) suggested LLO-elicited Ca(2+) flux as the underlying mechanism. In addition, HUVEC incubation with EGD turned out to be a potent stimulus for sustained (>12-h) upregulation of proinflammatory cytokine generation (interleukin 6 [IL-6], IL-8, and granulocyte-macrophage colony-stimulating factor). Use of deletion mutants for LLO (EGD hly mutant), listerial phosphatidylinositol-specific phospholipase C (EGD plcA mutant), broad-spectrum phospholipase C (EGD plcB mutant) and internalin B (EGD inlB mutant), as well as purified LLO, identified LLO as largely responsible for the cytokine response. Endothelial cells responded with diacylglycerole and ceramide generation as well as nuclear translocation of NF-kappa B to the stimulation with the LLO-producing strains EGD and Listeria innocua. The endothelial PC-phospholipase C inhibitor tricyclodecan-9-yl-xanthogenate as well as two independent inhibitors of NF-kappa B activation, pyrolidine dithiocarbamate and caffeic acid phenethyl ester, suppressed both the NF-kappa B translocation and the upregulation of cytokine synthesis. We conclude that L. monocytogenes is a potent stimulus of NO release and sustained upregulation of proinflammatory cytokine synthesis in human endothelial cells, both events being largely attributable to LLO presentation. LLO-induced transmembrane Ca(2+) flux as well as a sequence of endothelial phospholipase activation and the appearance of diacylglycerole, ceramide, and NF-kappa B are suggested as underlying host signaling events. These endothelial responses to L. monocytogenes may well contribute to the pathogenic sequelae in severe listerial infection and sepsis.
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PMID:Human endothelial cell activation and mediator release in response to Listeria monocytogenes virulence factors. 1115 83

The pathological features of ascending gonococcal infection suggest that proinflammatory mediators secreted by tissue-resident macrophages are important components of the host response. Challenge of fully differentiated, mature macrophages with variants of Neisseria gonorrhoeae strain P9 or purified bacterial surface components (pili, lipooligosaccharide, and outer membrane vesicles) induced the secretion of interleukin 6 (IL-6), tumor necrosis factor alpha, growth-related protein alpha, macrophage inflammatory protein 1alpha (MIP-1alpha), and RANTES cytokines but had no effect on IL-8 production. No secretion of IL-1beta, epithelial-derived neutrophil attractant 78, granulocyte-macrophage colony-stimulating factor, IL-10, or IL-12 cytokines was observed. Notably, the P9-Opa(b) protein, in comparison to P9-Opa(a), increased the association of gonococci with macrophages and elevated the secretion of cytokines. Thus, variation in Opa protein expression by the gonococcus may be a determining factor in the severity of pelvic inflammatory disease.
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PMID:Interactions of Neisseria gonorrhoeae with mature human macrophage opacity proteins influence production of proinflammatory cytokines. 1117 72


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