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)

Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
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PMID:Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. 934 17

Fas, a member of the tumor necrosis factor (TNF ) receptor superfamily is a critical downregulator of cellular immune responses. Proinflammatory cytokines like interferon-gamma (IFN-gamma) and TNF-alpha can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Transforming growth factor-beta1 (TGF-beta1 ) is an essential anti-inflammatory cytokine, thought to play a key role in regulating hematopoiesis. In the present studies we investigated whether TGF-beta1 might regulate growth suppression and apoptosis of murine hematopoietic progenitor cells signaled through Fas. In the presence of TNF, activation of Fas almost completely blocked clonogenic growth of lineage-depleted (Lin-) bone marrow (BM) progenitor cells in response to granulocyte-macrophage colony-stimulating factor (GM-CSF ), CSF-1, or a combination of multiple cytokines. Whereas TGF-beta1 alone had no effect or stimulated growth in response to these cytokines, it abrogated Fas-induced growth suppression. Single-cell studies and delayed addition of TGF-beta1 showed that the ability of TGF-beta1 to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect through potentially contaminating accessory cells. Furthermore, TGF-beta1 blocked Fas-induced apoptosis of Lin- BM cells, but did not affect Fas-induced apoptosis of thymocytes. TGF-beta1 also downregulated the expression of Fas on Lin- BM cells. Thus, TGF-beta1 potently and directly inhibits activation-dependent and Fas-mediated growth suppression and apoptosis of murine BM progenitor cells, an effect that appears to be distinct from its ability to induce progenitor cell-cycle arrest. Consequently, TGF-beta1 might act to protect hematopoietic progenitor cells from enhanced Fas expression and function associated with proinflammatory responses.
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PMID:Transforming growth factor-beta1 abrogates Fas-induced growth suppression and apoptosis of murine bone marrow progenitor cells. 934 22

Culturing cord blood CD34+ cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha for 12 days, and stem cell factor (SCF) for 5 days, resulted in a 40- +/- 26-fold expansion in cell numbers, with 38 +/- 20% dendritic cells (DCs). Interleukin (IL)-4 and IL-13, which share properties, were examined first. Adding either one to the former baseline condition beginning on day 0 halved cell growth while the percentage of DCs increased to 60-70%, resulting in unchanged DC yields. Delaying use of IL-4 or IL-13 to day 5 led to 25-fold cell expansion with approximately 80% DC, the yield of which was then twofold over that of baseline control cultures, while numbers of other cells decreased. IL-4 and IL-13 had no additive or antagonistic effect on DC generation. The effect of Flt3 ligand (FL), known to enhance proliferation of hematopoietic progenitors induced by other growth factors, was examined next. FL added alone induced DC in the same manner as SCF. Using both FL and SCF throughout the culture period enhanced total cell recovery fourfold above that of baseline control cultures on day 12 compared with > or =2.5-fold if either one was stopped on day 5. When both FL and SCF were used for 12 days, DC recovery was fivefold that of control cultures, whereas it was to three- to 3.5-fold when either one was stopped on day 5. A similar trend was noted for CD15+ cells, and, to a lesser extent, for CD14+ cells. Finally, using SCF and FL for 12 days, with IL-4 or IL-13 added from day 5 onwards, led to comparably enhanced cell yields relative to control cultures with approximately 60% DC. These data underline the need to use appropriate cytokine combinations and schedules to optimize generation of DCs from CD34+ progenitors. Associated with GM-CSF and TNF-alpha, IL-4 or IL-13 promotes differentiation and maturation of DCs over other myeloid cells. Under the same baseline conditions, FL appears to potentiate SCF throughout the culture period, inducing proliferation and development of DC as well as of other myeloid cells.
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PMID:The influence of interleukin (IL)-4, IL-13, and Flt3 ligand on human dendritic cell differentiation from cord blood CD34+ progenitor cells. 1002 79

ONO-4007 is a synthetic lipid A analog that exhibits strong antitumor activity in several animal models via intratumoral production of tumor necrosis factor (TNF). In the present study the cytokine-inducing effect of ONO-4007 was investigated in human monocytes that were freshly isolated or had been incubated for 3 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor. ONO-4007 induced slight production of TNF-alpha, Interleukin (IL)-1 beta, IL-6 and IL-12 in fresh monocytes but strongly induced TNF-alpha production in GM-CSF-treated monocytes. Monocytes treated with macrophage colony-stimulating factor were also primed to produce TNF-alpha in response to ONO-4007. In the production of IL-1 beta, IL-6 and IL-12, GM-CSF did not show a priming effect. In contrast to ONO-4007, lipopolysaccharide (LPS) induced significant amounts of all these cytokines in fresh monocytes. In whole blood, ONO-4007 failed to induce TNF-alpha, whereas LPS and LA-15-PP (Escherichia coli-type lipid A) strongly induced TNF-alpha production. In the GM-CSF-treated monocytes, both elimination of serum from the culture medium and anti-CD14 antibody treatment attenuated LPS-induced TNF-alpha production but not ONO-4007-induced TNF-alpha production. This study shows that ONO-4007 activates human monocytes/ macrophages to release TNF-alpha only in a primed state and suggests that ONO-4007 would activate these cells via different pathways from LPS. These differences could mean that ONO-4007 has potent antitumor activity with lower toxicity than LPS.
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PMID:ONO-4007, an antitumor lipid A analog, induces tumor necrosis factor-alpha production by human monocytes only under primed state: different effects of ONO-4007 and lipopolysaccharide on cytokine production. 943 77

Culture conditions for human dendritic cells (DC) have been developed by several laboratories. Most of these culture methods, however, have used conditions involving fetal calf serum (FCS) to generate DC in the presence of granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. Recently, alternative culture conditions have been described using an additional stimulation with monocyte-conditioned medium (MCM) and FCS-free media to generate DC. As MCM is a rather undefined cocktail, the yield and quality of DC generated by these cultures varies substantially. We report that a defined cocktail of tumor necrosis factor (TNF)-alpha, IL-1beta and IL-6 equals MCM in its potency to generate DC. Addition of prostaglandin (PG)E2 to the cytokine cocktail further enhanced the yield, maturation, migratory and immunostimulatory capacity of the DC generated. More importantly, culture conditions also influenced the outcome of the T cell response induced. DC cultured with TNF-alpha/IL-1/IL-6 or MCM alone induced CD4+ T cells that release intermediate levels of interferon (IFN)-gamma and no IL-4 or IL-10. Production of IFN-gamma was significantly induced by addition of PGE2, while no effect on production of IL-4 or IL-10 was observed. Even more striking differences were observed for CD8+ T cells. While MCM conditions only induced IFN-gamma(low), IL-4(neg) cells, TNF-alpha/IL-1/IL-6 promoted growth of IFN-gamma(intermediate), IL-4(neg) CD8+ T cells. Addition of PGE2 again only further polarized this pattern enhancing IFN-gamma production by alloreactive CD8+ T cells in both cultures without inducing type 2 cytokines. Taken together, the data indicate that the defined cocktail TNF-alpha/IL-1/IL-6 can substitute for MCM and that addition of PGE2 further enhances the yield and quality of DC generated. TNF-alpha/IL-1, IL-6 + PGE2-cultured DC seem to be optimal for generation of IFN-gamma-producing CD4/CD8+ T cells.
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PMID:Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. 946 98

We have defined conditions for generating large numbers of dendritic cells (DC) in marrow cultures from 10-12-week-old ACI or WF rats. The combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-alpha, known to induce DC from human CD34+ progenitors, was not effective with rat. In contrast, GM-CSF plus IL-4 generated DC in high yield, corresponding to 30-40% of the initial number of plated marrow cells. The DC proliferated in distinctive aggregates, in which most cells had an immature phenotype marked by undetectable surface B7 and high levels of MHC class II products within intracellular lysosomes. When dislodged and dispersed, the aggregates gave rise to mature stellate DC with abundant surface MHC class II and B7, sparse MHC class II- lysosomes, and strong T cell-stimulating capacity. Therefore, rat marrow progenitors can generate large numbers of immature DC, with abundant intracellular MHC class II compartments, and potent, stimulatory, mature DC.
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PMID:Generation or large numbers of immature and mature dendritic cells from rat bone marrow cultures. 954 75

Immunization with nucleic acids has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. We hypothesize that immunization with DNA could be enhanced by directing specific immune responses induced by the vaccine based on the differential correlates of protection known for a particular pathogen. Recently we and others reported that specific immune responses generated by DNA vaccine could be modulated by co-delivery of gene expression cassettes encoding for IL-12, granulocyte-macrophage colony-stimulating factor and the co-stimulatory molecule CD86. To further engineer the immune response in vivo, we investigated the induction and regulation of immune responses following the co-delivery of pro-inflammatory cytokine (IL-1 alpha, TNF-alpha, and TNF-beta), Th1 cytokine (IL-2, IL-12, IL-15, and IL-18), and Th2 cytokine (IL-4, IL-5 and IL-10) genes. We observed enhancement of antigen-specific humoral response with the co-delivery of Th2 cytokine genes IL-4, IL-5, and IL-10 as well as those of IL-2 and IL-18. A dramatic increase in antigen-specific T helper cell proliferation was seen with IL-2 and TNF-alpha gene co-injections. In addition, we observed a significant enhancement of the cytotoxic response with the co-administration of TNF-alpha and IL-15 genes with HIV-1 DNA immunogens. These increases in CTL response were both MHC class I restricted and CD8+ T cell dependent. Together with earlier reports on the utility of co-immunizing using immunologically important molecules together with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.
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PMID:Modulation of amplitude and direction of in vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens. 954 5

The development of dendritic cells (DC) is still only partly understood. Recently established culture systems using CD34+ cells or monocytes as precursor cells for the generation of DC indicate the necessity of pro-inflammatory cytokines for their development. In vivo the contact to other cells or to the proteins of the extracellular matrix might also be essential for their development. In our experiments we used granulocyte-macrophage colony-stimulating factor- and IL-4-treated human monocytes as precursor cells to investigate the interaction of DC at different maturation stages with the matrix proteins fibronectin, collagen type I and collagen type IV. We demonstrate a strong beta1-integrin-mediated adherence of immature DC to fibronectin that is lost completely during maturation. The binding to collagen type I was less strong but induced a maturation of the precursor cells. After 3 days of culture on this protein, the cells showed all features of fully matured DC such as expression of CD83 and an excellent allostimulatory capacity. The reason for this effect was shown to be the induction of TNF-alpha production by the DC themselves. In contrast to the adhesion to fibronectin, the maturation and the cytokine production of DC induced by collagen type I could not be inhibited by blocking of beta1-integrins. These results indicate that proteins of the extracellular matrix play an important role in the development and function of human DC.
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PMID:Influence of extracellular matrix proteins on the development of cultured human dendritic cells. 960 74

The effects of n-6 and n-3 polyunsaturated fatty acids (PUFA) on protein metabolism, cell-mediated immunity, and production of cytokines and prostanoids were studied in experimental animals and patients with esophageal cancer. In the experimental study using a rat burn model, n-6 PUFA increased serum interleukin-6 (IL-6) and tumor necrosis factor (TNF), alpha (P < 0.05), and decreased nitrogen balance (NB) (P < 0.05), when compared with a fat-free control. But addition of n-3 PUFA reduced TNF-alpha and IL-10 (P < 0.05) and improved NB (P < 0.05). Suppressed delayed type hypersensitivity (DTH) induced by burn injury, which was not influenced by n-6 PUFA, was significantly improved by the administration of n-3 PUFA. n-6 PUFA tended to increase, and n-3 PUFA significantly decreased the endotoxin translocation. DTH, granulocyte-macrophage colony-stimulating factor, and eicosapentaenoic acid (EPA) content increased proportionately with the intravenous dose of fish oil emulsion. The effects of n-6 and n-3 PUFA were studied in the patients who underwent surgery for esophageal cancer. In the group of patients fed by total parenteral nutrition with soybean oil emulsion, the serum IL-6 significantly increased at 2 and 6 h after operation (P < 0.05). Oral/enteral supplementation of EPA ethyl ester (1.8 g/d) significantly reduced the postoperative IL-6 production (P < 0.05 at 1, 2, and 6 h after operation), and improved cell-mediated immune function 3 wk after operation (P = 0.05). During the chemoradiation therapy, cell-mediated immune function was improved significantly in the patients fed enterally with EPA ethyl ester (n = 5), when compared with the patients without EPA (n = 14).
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PMID:n-3 versus n-6 polyunsaturated fatty acids in critical illness. 964 1

Human endothelium is capable of expressing a variety of molecules, including cytokines and growth factors, critical to inflammation. This aspect of coronary endothelium has not been studied in detail. In this study, we report, for the first time, expression of multifunctional cytokines by human coronary artery endothelial cells (HCAEC) and their regulation by inflammatory cytokines and glucocorticoids. We also compared expression of cytokine transcripts in two additional cell lines derived from pulmonary artery (HPAEC) and umbilical vein (HUVEC) endothelium. HCAEC expressed transcripts for interleukin 5 (IL-5), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) constitutively. Induction of IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1 was seen following treatment with TNFalpha. We found no expression of IL-1RA, IL-2, IL-4, IL-13, TNF-alpha, or IFN-gamma in HCAEC. IL-1beta and TNF-alpha synergistically induced IL-6 and GM-CSF and additively induced IL-8 and MCP-1 production, while IL-2, IL-10, IFN-alpha, and IFN-gamma had little or no additional effects. Interestingly, no IL-1alpha or IL-5 protein product was found even after maximal stimulation of HCAEC. No significant differences were seen in the profile of cytokine genes expressed by HCAEC, HPAEC, or HUVEC. Glucocorticoids inhibited IL-8 production from all three cell lines. This study demonstrates that human coronary endothelial cells are capable of expressing a wide variety of multifunctional cytokines which may be of relevance to vascular inflammation.
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PMID:Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids. 965 19


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