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)

Monocytic cells have been shown to produce endothelin, a potent vasoconstrictor molecule with immune modulating properties. The signalling mechanisms involved in this response are presently unclear. Monocytes are also believed to play an important role in inflammatory bowel disease (IBD). The objective of this study was to characterize the role of various cytokines, bacterial lipopolysaccharide (LPS) and colony-stimulating factors on the production of endothelin (ET) by freshly isolated human monocytes. Compelling circumstantial evidence exists for the conditions being investigated occurring in inflamed bowel mucosa to where monocytes migrate. Whereas LPS stimulated the release of 7 pg ET/2x106 cells in 40 hr, interferon-gamma (IFN-gamma) stimulated 45 pg ET/2x106 cells in 40 hr. There was an additive response when the two stimuli were employed together. Significantly the addition of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) effected a two- to threefold, dose-dependent increase in the production of ET. Production of endothelin was reproducibly blocked by the addition of the protein kinase C (PKC) inhibitors staurosporine and H7, as well as by the protein synthesis inhibitor cycloheximide. Assessment of the activities of the alpha and beta isoforms of conventional protein kinase C (PKC), as determined by MonoQ column fractionated calcium and lipid activatible phosphotransferase activity towards myelin basic protein (MBP) revealed an additive effect of using LPS, IFN-gamma and GM-CSF, which was even greater than that demonstrated for phorbol myristate acetate (PMA). Additionally the secretion of ET by monocytes from Crohn's disease patients (in remission) was analysed and compared with an age-matched control group. There was no significant difference between the two. These results: (1) demonstrate an important synergistic role for GM-CSF and IL-3 in the predominantly IFN-gamma-mediated ET production by normal human monocytes; (2) indicate a possible role for the protein kinase C signalling pathway in this response; and (3) argue against a primary abnormality of ET production in peripheral monocytes from patients with Crohn's disease.
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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 potentiate interferon-gamma-mediated endothelin production by human monocytes: role of protein kinase C. 982 13

Mucosal macrophages have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Macrophage-colony stimulating factor (M-CSF) influences monocyte/macrophage proliferation, differentiation, and activation. Serum levels are increased in active IBD, but little is known about its role in mucosal inflammation. This study was undertaken to determine the distribution, frequency, and level of M-CSF expression in normal and IBD-affected intestine. RNA and tissue were studied from patients with Crohn's disease (CD) and ulcerative colitis (UC) as well as from histologically normal colon. Tissue from intestinal tuberculosis and ischaemic colitis patients served as controls. M-CSF mRNA and protein were examined by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridisation, and immunohistochemistry, respectively. M-CSF mRNA and protein were detected in histologically normal intestine, but their expression was largely confined to the mucosa. In active IBD, the frequency of M-CSF-expressing cells was significantly increased and their distribution markedly altered, although no increase in mucosal M-CSF mRNA levels in intestinal tissue was observed. The changes were not specific to IBD, as there were similar findings in intestinal tuberculosis and ischaemic colitis. The marked alteration observed in M-CSF expression in IBD and the importance of this cytokine in stimulating macrophage functions suggest that M-CSF may contribute to the pathogenesis of the IBD lesion.
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PMID:Expression of macrophage-colony stimulating factor in normal and inflammatory bowel disease intestine. 1174 98

Treatment for Crohn's disease is aimed at immunosuppression. Yet inherited disorders associated with defective innate immunity often lead to development of a Crohn's-like disease. We performed an open-label dose-escalation trial (4-8 microg/kg per day) to investigate the safety and possible benefit of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of 15 patients with moderate to severe Crohn's disease. No patients had worsening of their disease. Adverse events were negligible and included minor injection site reactions and bone pain. Patients had a significant decrease in mean Crohn's disease activity index (CDAI) score during treatment (p<0.0001). After 8 weeks of treatment, mean CDAI had fallen by 190 points. Overall, 12 patients had a decrease in CDAI of more than 100 points, and eight achieved clinical remission. Retreatment was effective, and treatment was associated with increased quality-of-life measures. GM-CSF may offer an alternative to traditional immunosuppression in treatment of Crohn's disease.
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PMID:Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. 1460 56

Neutropenia and its subsequent infectious complications represent the most common dose-limiting toxicity of cancer chemotherapy. Febrile neutropenia (FN) occurs with common chemotherapy regimens in 25 to 40% of treatment-naive patients, and its severity depends on the dose intensity of the chemotherapy regimen, the patient's prior history of either radiation therapy or use of cytotoxic treatment, and comorbidities. The occurrence of FN often causes subsequent chemotherapy delays or dose reductions. It may also lengthen hospital stay, increase monitoring, diagnostic and treatment costs, and reduce patient quality of life. A decade after their introduction, colony-stimulating factors (CSFs) such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are now an integral part of the prevention of potentially life-threatening FN; however, only G-CSF has US Food and Drug Administration approval for use in chemotherapy-induced neutropenia. These adjunctive agents accelerate formation of neutrophils from committed progenitors, thereby reducing the duration and severity of neutropenia. Important uses of CSFs in oncology are prevention of FN after chemotherapy, treatment of febrile neutropenic episodes and support following bone marrow transplantation, and collection of CSF-mobilised peripheral blood progenitor cells. G-CSF is used more frequently than GM-CSF for all of these indications because of fewer associated adverse effects. Clinical trials to date have not demonstrated a significant effect on overall survival or disease-free survival, which is most likely to be due to small sample size and lack of power to prove effect. However, they have demonstrated clinical utility in allowing the delivery of planned chemotherapy dose on schedule, an important clinical goal especially in curative tumour settings. The high cost of these agents limits their widespread use. Current American Society of Clinical Oncology guidelines recommend primary prophylaxis, or first cycle use, with CSFs being confined to patients with > or = 40% risk of FN, which may include elderly patients and other high-risk patients. In addition to the risk of FN, primary prophylaxis should also be considered if the patient has risk factors that place them in the Special Circumstances category. These risk factors may include decreased immune function in patients who are already at an increased risk of infection and pre-existing neutropenia due to disease, extensive prior chemotherapy, or previous irradiation to the pelvis or other areas containing large amounts of bone marrow. Future studies are needed to better define the patients most likely to benefit from CSF therapy, both for prophylaxis and as an adjunct to antibiotics for treatment of FN. Other potential uses include combination therapy with stem cell factors and other cytokines to boost progenitor cell development, maintaining dose intensity of salvage therapy in metastatic cancer patients, and application in patients with pneumonia, Crohn's fistulas, diabetic foot infections and a variety of other infectious conditions.
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PMID:Colony-stimulating factors for the management of neutropenia in cancer patients. 1247 91

Infliximab, a chimeric antibody to tumour necrosis factor-alpha (TNF-alpha), holds much promise for the treatment of patients with Crohn's disease. On the cellular level, infliximab affects survival and, as presented by Agnholt et al. in this issue of the journal, inhibits GM-CSF (granulocyte-macrophage colony-stimulating factor) production by intestinal T lymphocytes. Future studies will reveal whether the pro-apoptotic effect of infliximab is linked to its inhibition of endogenous GM-CSF expression in T cells. Treatment of Crohn's disease, a severe chronic intestinal disorder, may at times be challenging as it can be refractory to routine therapy. Among novel therapeutic strategies, agents that neutralize tumour necrosis factor-alpha (TNF-alpha) are of particular interest because of the crucial role of TNF-alpha in sustaining chronic mucosal inflammation. The exact mechanism of the anti-TNF action, apart from direct activity that neutralizes cytokines, is not fully understood. Cellular effects of TNF-alpha neutralizing treatment include an increased susceptibility to apoptosis of intestinal mucosal T cells. A novel pathway of anti-TNF-alpha interaction with T cells has been presented in the current issue of this journal. Agnholt et al. have found that in-vivo or in-vitro administration of infliximab, a chimeric antibody to TNF-alpha, resulted in a decreased production of GM-CSF (granulocyte-macrophage colony-stimulating factor) by T cells. Infliximab related down-regulation of TNF-alpha induced GM-CSF expression may be one of the mechanisms by which this drug increases the rate of apoptosis in T cells.
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PMID:Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease. 1520 77

The chimeric monoclonal antibody to tumor necrosis factor (TNF), infliximab, is an effective therapy for Crohn's disease. However, the formation of human anti-chimeric antibodies to infliximab (immunogenicity) can lead to loss of efficacy as well as acute infusion reactions and delayed hypersensitivity reactions. The fully human monoclonal antibody adalimumab and the pegylated humanized monoclonal antibody fragment CDP870 are biologic therapies against TNF that might be effective for Crohn's disease and less immunogenic than infliximab. Other potential alternatives to infliximab for Crohn's disease include the humanized anti-adhesion molecule antibodies natalizumab and MLN-02, the humanized anti-interleukin 12 antibody ABT-874, the humanized anti-interferon g antibody fontolizumab, the humanized anti-interleukin 6 receptor antibody MRA, and human recombinant granulocyte macrophage colony stimulating factor (sargramostim). Some, or all, of these therapies will likely represent important treatments for Crohn's disease in the future.
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PMID:How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn's disease. 1558 28

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates proliferation, differentiation, and function of hematopoietic progenitor cells. Aside from expansion of hematopoietic cells, GM-CSF has shown efficacy in other diseases, including Crohn's disease. While GM-CSF being clinically used in humans, the ability to perform mechanistic studies in murine models is difficult due to the limited availability and rapid clearance of murine GM-CSF in the peripheral blood. To address these issues, we efficiently expressed murine GM-CSF under the control of the AOX1 gene promoter in Pichia pastoris using the Mut(S) strain KM71H. We describe the unique conditions that are required for efficient production by high-density fermentation and purification of mGM-CSF protein. Recombinant mGM-CSF protein was purified by tangential flow ultrafiltration and preparative reverse phase chromatography. To address limited half life or rapid clearance in mice, recombinant murine GM-CSF was modified by lysine-directed polyethylene glycol conjugation (PEGylation). PEG-modified and unmodified proteins were characterized by amino terminus sequence analysis and matrix assisted laser desorption ionization time-of-flight mass spectrometry. Under the mild reaction conditions, the recombinant protein is efficiently modified by PEGylation on an average of 2-3 sites per molecule. In vivo treatment of mice with PEGylated mGM-CSF, but not the unmodified recombinant mGM-CSF, reproduces the potent colony stimulating effects of human GM-CSF in patients on myeloid progenitor populations, as assessed by FACs analysis. This simplified approach for the expression, purification, and modification of a biologically potent form of murine GM-CSF should facilitate the study of central mechanisms of action in murine disease models.
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PMID:PEGylated murine Granulocyte-macrophage colony-stimulating factor: production, purification, and characterization. 1621 50

The aim of this in vitro study was to evaluate the intracellular redox state and respiratory burst (RB) in neutrophils of patients with Crohn's disease (CD). The intracellular redox state and RB in neutrophils was assessed by the superoxide anion (O2*-) production induced in these cells after stimulation by various factors related to the molecular mechanisms that, if altered, may be responsible for an abnormal immune response. This can, in part, cause the onset of inflammation and tissue damage seen in CD. This study demonstrated a decreased glutathione/glutathione disulfide (GSH/GSSG) ratio index of an increased oxidative state in CD patient neutrophils. Moreover, our findings showed a decrease in tumor necrosis factor (TNF-alpha)- or phorbol 12-myristate 13-acetate (PMA)-induced O2*- production in CD patient neutrophils adherent to fibronectin as compared with controls. A decreased adhesion was also demonstrated. For this reason, the involvement of altered mechanisms of protein kinase C (PKC) and beta-integrin activation in CD patient neutrophils is suggested. These data also showed that the harmful effects of TNF-alpha cannot be caused by excessive reactive oxygen species (ROS) production induced by neutrophils. Decreased cell viability after a prolonged time of adhesion (20 hrs) was also measured in CD patient neutrophils. The findings of this study demonstrate, for the first time, that granulocyte-macrophage colony-stimulating factor (GM-CSF), a compound recently used in CD therapy, is able to activate the RB for a prolonged time both in control and CD patient neutrophils. Increased viability of CD patient neutrophils caused by GM-CSF stimulation was also observed. In conclusion, our results indicate that decreased O2*- production and adhesion, caused, in part, by an anomalous response to TNF-alpha, together with low GSH level and low cell viability, may be responsible for the defective neutrophil function found in CD patients. This can contribute to the chronic inflammation and relapses that characterize this pathology. A possible role of GM-CSF in inducing O2*- production and in restoring the defensive role of neutrophils in CD patients is suggested.
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PMID:Redox state and O2*- production in neutrophils of Crohn's disease patients. 1644 95

With recent advances in the understanding of its pathophysiology, inflammatory bowel disease has become a very active area for the development of novel therapeutic agents. New targets for biologics include cytokines involved in T-cell activation, with antibodies directed against IL-12 and interferon-gamma. Selective adhesion molecule blockade has produced promising, though mixed, results. Recombinant human granulocyte-macrophage colony-stimulating factor might be effective in active Crohn's disease, presumably through stimulation of intestinal innate immune responses. With increasing evidence for a crucial role for luminal flora in maintaining the health of the bowel, strategies to manipulate intestinal bacteria using probiotics and prebiotics are being actively investigated as well.
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PMID:Evolving knowledge and therapy of inflammatory bowel disease. 1651 73

Inflammatory bowel disease (IBD) has been the subject of recent intense research and development. A greater insight into the basic pathological mechanisms of ulcerative colitis (UC) and Crohn's disease (CD) has resulted in the emergence of more sophisticated and effective management options. Additionally, established therapies are attracting renewed interest with novel dosage regimens and new formulations offering improved efficacy whilst maintaining an excellent tolerance profile. High dose 5-aminosalicylic acid (5-ASA) has been a focus for investigation in recent clinical trials. The ASCEND study, which compared a 4.8 g/day dose with a 2.4 g/day dose, demonstrated that high dose mesalazine was significantly superior in achieving treatment success and symptom control, whilst maintaining a comparable tolerance and safety profile. The development of biotechnology agents targeted against tumour necrosis factor (TNF) provides promise of new treatment options in both CD and UC. The efficacy of CDP571, adalimumab and certolizumab have been investigated in CD, and infliximab, which is currently approved as an agent in inflammatory and fistulizing CD, has also been recently investigated in UC. Investigational pipeline molecules such as natalizumab, MLN-02, an anti-interleukin 12 antibody and sargramostim, have also shown encouraging results from early studies and are now undergoing evaluation in large clinical trials.
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PMID:What's new: innovative concepts in inflammatory bowel disease. 1659 57


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