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)

Dendritic cell (DC) precursors and immature DC reside in epithelium where they encounter pathogens and cytokines, which stimulate their differentiation. We hypothesized that type-I interferons (IFN-alpha and -beta), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine this possibility, we used an in vitro model of DC differentiation in which initial culture of human CD14(+) monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)-alpha drives the final development into mature DC. We found in this model that IFN-alpha/beta, added from the initiation of the culture on, significantly reduced the survival and altered the morphology and differentiation of DC. TNF-alpha-dependent maturation of IFN-beta-treated immature DC led to cells with reduced expression of CD1a, CD40, CD54, and CD80 when compared with mature DC controls. IFN-alpha/beta-treated DC further had a reduced capacity to induce naive Th-cell proliferation through allostimulation or anti-CD3 monoclonal antibody stimulation. In addition, IFN-alpha/beta-treated DC secreted less IL-12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4(+) T cells, and this decrease correlated directly with their inability to support CD4(+) T-cell secretion of IFN-gamma, even though T-cell lymphotoxin production was unaffected. These findings indicate that type-I IFNs can influence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function.
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PMID:Interferon-alpha and -beta inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14(+) precursors. 1089 53

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-beta. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.
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PMID:Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression. 1142 38

Both type I interferons (IFNs) as well as lipopolysaccharide (LPS) individually compromise selected monocytic or dendritic cell (DC) functions. This study investigates the influence of these agents on the differentiation and the regulation of cell death of monocyte-derived DCs generated in the presence of granulocyte-macrophage colony-stimulating factor plus interleukin-4 (IL-4). It is reported that excessive apoptosis occurred rapidly in monocyte-derived DC cultures, if IFN-alpha or IFN-beta was added in combination with LPS or lipoteichoic acid (LTA). The small fraction of cells surviving in such cultures displayed a mature DC phenotype with expression of CD83, CD80, and CD86. IL-10 was found in the supernatants of monocyte-derived DC cultures, if supplemented with LPS or IFN-alpha plus LPS but not in control cultures. When monocyte-derived DCs were generated in the presence of IFN-alpha without LPS, these cells displayed an immature DC phenotype with a reduction of cell recovery but no overt apoptosis. However, the addition of LPS, LTA, LPS plus IFN-gamma, or tumor necrosis factor alpha (TNF-alpha) plus prostaglandin E2 to such cells again resulted in the rapid induction of apoptosis in the majority of cells, together with a reduced production of IL-12 p70 and TNF-alpha. Together, these data indicate an exquisite sensitivity of monocyte-derived DCs to activation-induced cell death if generated in the presence of IFN-alpha, indicating the existence of an important mechanism of immunosuppression caused by IFN-alpha-inducing agents, such as viral or bacterial stimuli. (Blood. 2001;98:736-742)
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PMID:Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells. 1146 74

Pseudomonas aeruginosa infection, one of the major complications of burn wounds, may lead to sepsis and death. Using the Multi-Probe Template/RNase protection assay, we have compared the expression of different cytokine genes within the skin and livers of thermally injured mice infected with P. aeruginosa PAO1. Thermal injury alone enhanced or up-regulated certain cytokines, including macrophage colony-stimulating factor (M-CSF), interleukin 1 (IL-1)RI, IL-1 beta, macrophage inflammatory protein (MIP)-1 beta and MIP-2; while PAO1 challenge alone up-regulated tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) expression. The combination of thermal injury plus PAO1 infection enhanced the expression of several pro-inflammatory and haematopoietic cytokines [stem cell factor (SCF), leukocyte inhibitory factor (LIF), IL-6 and TNF-alpha]; induced the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF by 5 h and the expression of additional cytokines, including TGF-beta, TNF-beta, lymphotoxin beta (LT-beta), interferon gamma (IFN-gamma), and IFN-beta by 40 h post-burn/infection. While the most intense cytokine expression occurred in the skin, the majority of cytokines tested were also expressed in the liver by 40 h post-burn/infection. These results suggest that in P. aeruginosa infection of burn wounds: (1) up-regulation of the expression of different cytokines, locally and within the livers of burned mice, is an indication of P. aeruginosa -induced sepsis; and (2) IL-6 and G-CSF play an important role in the host response mechanism.
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PMID:The effects of infection of thermal injury by Pseudomonas aeruginosa PAO1 on the murine cytokine response. 1179 26

In the absence of survival-inducing cytokines activated T cells and neutrophils enter apoptosis spontaneously. Phosphatidylinositol 3-kinase (PI3 K) activation and signaling through PKB/AKT have been widely linked to the inhibition of apoptosis by cytokines. Here we have investigated the role of PKB in the inhibition of spontaneous apoptosis of activated human CD4+ T cells and neutrophils. We used a range of cytokines known to induce survival and/or activation of PKB. We found activation of PKB in T cells treated with IL-2 and insulin, and neutrophils cultured with N-formyl-Met-Leu-Phe (fMLP), insulin or granulocyte-macrophage colony-stimulating factor. Insulin did not inhibit apoptosis in neutrophils or T cells and fMLP did not delay neutrophil apoptosis. Intriguingly, IFN-beta induced PI3 K-dependent survival in both cell types, but did not activate PKB. IL-2 mediated rescue of T cells from apoptosis but no induction of proliferation occurred in thepresence of LY294002, an inhibitor of PI3 K, which also blocked subsequent PKB activation. The main role of PI3 K in IL-2-mediated signaling may therefore be in the regulation of proliferation. These findings suggest that activation of PKB and inhibition of apoptosis can be dissociated in cytokine-mediated rescue of non-transformed CD4+ T cells and neutrophils.
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PMID:Cytokine-mediated inhibition of apoptosis in non-transformed T cells and neutrophils can be dissociated from protein kinase B activation. 1182 65

During pregnancy, a complex cytokine network is present at the maternal-fetal interface in order to support normal growth and development of the placenta and fetus. HIV can frequently infect placental trophoblast but the impact of cytokines produced locally by the placenta and decidua on virus expression and replication is unknown. We comprehensively assayed the cytokines typically present in the placental microenvironment for their potential to modulate HIV transcriptional activation in the isolated trophoblast cells employing a transient transfection assay with luciferase as a reporter gene. Long terminal repeats (LTRs) of two divergent virus strains, HIV-1 LAI and HIV-1 NDK, were used to analyze virus-specific features. Four cytokines, epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF-alpha), were found to stimulate promoters of both viruses, whereas interferon alpha (IFN-alpha) and IFN-beta were found to suppress the transcription driven from both promoters. The differences observed between the two viruses did not reach a statistically significant level. None of the remaining cytokines, including EGF; GM-CSF; insulin-like growth factor I (IGF-I); IFN-alpha, IFN-beta, and IFN-gamma; IL-1 alpha, IL-1 beta, IL-2, IL-6, and IL-10; leukemia inhibitory factor (LIF); macrophage colony-stimulating factor (M-CSF); platelet-derived growth factor BB (PDGF-BB); transforming growth factor beta (TGF-beta); and TNF-alpha, affected transcriptional expression of the promoter constructs. Our results demonstrate that the local balance of cytokines may be critical for activation of HIV in the syncytiotrophoblast-cytotrophoblast layer and thus play an important role in the transmission of virus across the placental barrier.
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PMID:Role of placental cytokines in transcriptional modulation of HIV type 1 in the isolated villous trophoblast. 1220 6

Cytokines play an important role in controlling the homoeostasis of the immune system. Infection with HIV results in dysregulation of the cytokine profile in vivo and in vitro. During the course of HIV-1 infection secretion of T-helper type 1 (Th1) cytokines, such as interleukin (IL)-2, and antiviral interferon (IFN)-gamma, is generally decreased, whereas production of T helper type 2 (Th2) cytokines, IL-4, IL-10, proinflammatory cytokines (IL-1, IL-6, IL-8) and tumour necrosis factor (TNF)-alpha, is increased. Such abnormal cytokine production contributes to the pathogenesis of the disease by impairing cell-mediated immunity. A number of cytokines have been shown to modulate in vitro HIV-1 infection and replication in both CD4 T lymphocytes and cells of macrophage lineage. HIV-inductive cytokines include: TNF-alpha, TNF-beta, IL-1 and IL-6, which stimulate HIV-1 replication in T cells and monocyte-derived macrophages (MDM), IL-2, IL-7 and IL-15, which upregulate HIV-1 in T cells, and macrophage-colony stimulating factor, which stimulates HIV-1 in MDM. HIV-suppressive cytokines include: IFN-alpha, IFN-beta and IL-16, which inhibit HIV-1 replication in T cells and MDM, and IL-10 and IL-13, which inhibit HIV-1 in MDM. Bifunctional cytokines such as IFN-gamma, IL-4 and granulocyte-macrophage colony-stimulating factor have been shown to have both inhibitory and stimulatory effects on HIV-1. The beta-chemokines, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES are important inhibitors of macrophage-tropic strains of HIV-1, whereas the alpha-chemokine stromal-derived factor-1 suppresses infection of T-tropic strains of HIV-1. This review outlines the interactions between cytokines and HIV-1, and presents clinical applications of cytokine therapy combined with highly active antiretroviral therapy or vaccines.
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PMID:Cytokines and HIV-1: interactions and clinical implications. 1295 22

Dendritic cells (DCs) represent a promising tool for immunotherapy. A key feature in their action is to provide co-stimulatory signals for full activation of T cells. In view of recent studies demonstrating the critical role of 4-1BB co-stimulation in T cell response, it is of importance to optimize 4-1BB ligand (4-1BBL) expression on human monocyte-derived DCs (MDDCs), the DC source of many clinical studies. In this study, two types of MDDCs, generated in granulocyte-macrophage colony-stimulating factor and interleukin-4 (GM-CSF/IL-4-DCs) or in interferon-beta and IL-3 (IFN-beta/IL-3-DCs), were analyzed for 4-1BBL expression in response to several known DC activators. Immature MDDCs expressed 4-1BBLs at very low levels. Lipopolysaccharide (LPS) was the only activator that preferentially triggered 4-1BBL expression on either MDDCs, but 4-1BBL-positive cells were significantly more frequently observed on LPS-activated GM-CSF/IL-4-DCs (30.2+/-2.6% versus 14.3+/-1.2%). Combinations of multiple activating signals did not bring about enhanced 4-1BBL stimulatory capacity. In addition, plasmid DNA transfection and necrotic cell pulsing of GM-CSF/IL-4-DCs for antigen loading also resulted in 4-1BBL up-regulation. However, in all circumstances, the induced 4-1BBL levels were low in comparison with CD80 co-stimulatory molecule. Finally, by demonstrating LPS-matured GM-CSF/IL-4-DCs from sorted 4-1BBL(high) population augmented T cell expansion and survival, we propose that efforts are required to increase 4-1BBL levels on MDDCs achieved by current activation schemes.
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PMID:Lipopolysaccharide preferentially induces 4-1BB ligand expression on human monocyte-derived dendritic cells. 1468 28

Type I interferons (IFNs) are potent regulators of both innate and adaptive immunity. All type I IFNs bind to the same heterodimeric cell surface receptor composed of IFN-alpha receptor (IFNAR-1) and IFN-alpha/beta receptor (IFNAR-2) polypeptides. This study revealed that type I IFN receptor levels vary considerably on hematopoietic cells, with monocytes and B cells expressing the highest levels. Overnight treatment of peripheral blood mononuclear cells (PBMCs) with IFN-alpha2b or IFN-beta led to increased expression on monocytes and B cells of surface markers commonly associated with activated antigen-presenting cells (APCs), such as CD38, CD86, MHC class I, and MHC class II. Five-day exposure of adherent monocytes to granulocyte-macrophage colony-stimulating factor (GM-CSF) plus IFN-alpha or IFN-beta caused the development of potent allostimulatory cells with morphology similar to that of myeloid dendritic cells (DCs) obtained from culture with GM-CSF and interleukin-4 (IL-4) but with distinct cell surface marker profiles and activity. In contrast to IL-4-derived DCs, IFN-alpha-derived DCs were CD14+, CD1a-, CD123+, CD32+, and CD38+ and expressed high levels of CD86 and MHC class II. Development of these cells was completely blocked by an antibody to IFNAR-1. Furthermore, activity of the type I IFN-derived DC in a mixed lymphocyte reaction (MLR) was consistently more potent than that of IL-4-derived DCs, especially at high responder/stimulator ratios. This MLR activity was abrogated by the addition of anti-IFNAR-1 antibody at the start of the DC culture. In contrast, there was no effect of anti-IFNAR-1 on IL-4-derived DCs, indicating that this is a distinct pathway of DC differentiation. These results suggest a potential role for anti-IFNAR-1 immunotherapy in autoimmune diseases, such as systemic lupus erythematosus (SLE), in which the action of excessive type I IFN on B cells and myeloid DCs may play a role in disease pathology.
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PMID:The receptor for type I IFNs is highly expressed on peripheral blood B cells and monocytes and mediates a distinct profile of differentiation and activation of these cells. 1498 77

Various dendritic cell subsets are induced from bone marrow cells under different cytokine conditions. We have demonstrated previously that the Th1-cytokine-conditioned bone marrow-derived dendritic cell (BMDC) subset BMDC1 (generated in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF] + interleukin [IL]-3 + interferon [IFN]-gamma+ IL-12) induces a much stronger type 1 immune response than BMDC0 (GM-CSF + IL-3). In the present study, we investigated the effect of 1alpha,25-dihydroxyvitamine D3 (VitD3), which is a known immunomodulating drug, on the differentiation of BMDC subsets. The addition of VitD3 significantly influenced the functional differentiation of BMDC1 compared with BMDC0. Specifically, the addition of VitD3 greatly decreased the expression levels of MHC class I, CD80, CD40 and leukocyte function-associated antigen (LFA)-1 molecules on BMDC1. In addition, VitD3-treated BMDC1 (VD3-BMDC1) almost completely lost their immunostimulating activity for inducing type 1 immunity and cytotoxic T lymphocyte generation. A failure in the induction of type 1 immunity by VD3-BMDC1 appeared to be due to the following: (i) the expression of co-stimulatory molecules on VD3-BMDC1 was strongly downmodulated compared with BMDC1 generated without VitD3; and (ii) VD3-BMDC1 showed significantly lower mRNA expression of IFN-gamma and IFN-beta, factors that are essential for cytotoxic T lymphocyte induction. VitD3 inhibited the differentiation of functionally competent BMDC1 during the early phase of differentiation but not during the late differentiation period. A possible reason for the inhibition of BMDC1 differentiation by VitD3 is reduced phosphorylation of STAT1 during early differentiation. Taken together, VitD3 strongly suppressed T-cell responses by inhibiting functional differentiation of precursor dendritic cells into functional BMDC1 that are feasible for inducing Th1-dependent cellular immunity.
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PMID:1alpha,25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation. 1644 25


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