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)

Granulocyte-macrophage colony-stimulating factor-differentiated bone marrow-derived dendritic cells were stimulated with the synthetic lipopeptide S-(2,3-bispalmitoyloxypropyl)-CGDPKHSPKSF (FSL-1) or the Escherichia coli lipopolysaccharide. FSL-1 induced the production of TNF-alpha and IL-12 by C57BL/6-derived bone marrow-derived dendritic cells but not by bone marrow-derived dendritic cells from Toll-like receptor 2-deficient (TLR2(-/-)) mice. Lipopolysaccharide induced the production of TNF-alpha and IL-12 by bone marrow-derived dendritic cells derived from either type of mice. FSL-1 did not induce production of IL-10 by bone marrow-derived dendritic cells from either type of mice, whereas lipopolysaccharide induced small amounts of IL-10 by bone marrow-derived dendritic cells from both types of mice. The upregulation by FSL-1 of the expression of CD80, CD86 and the MHC class II molecule IA(b) was dose- and time-dependent on the surfaces of C57BL/6-derived bone marrow-derived dendritic cells but not on the surface of TLR2(-/-)-derived bone marrow-derived dendritic cells. Lipopolysaccharide upregulated the expression of these molecules on the surfaces of bone marrow-derived dendritic cells from both types of mice. The expression of CD11c on the surfaces of C57BL/6-derived bone marrow-derived dendritic cells was upregulated by stimulation with both FSL-1 and lipopolysaccharide up to 12 h; thereafter, the expression was downregulated. The results suggest that FSL-1 can accelerate maturation of bone marrow-derived dendritic cells and this FSL-1 activity is mediated by TLR2.
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PMID:The synthetic analogue of mycoplasmal lipoprotein FSL-1 induces dendritic cell maturation through Toll-like receptor 2. 1642 Jun

Immediate precursors of the many subtypes of dendritic cells (DCs) remain obscure. Here we purified a splenic precursor population that produced all splenic CD8+ and CD8- conventional DCs (cDCs) but not plasmacytoid DCs or other lineages. This 'pre-cDC' population included cells 'precommitted' to form either CD8+ or CD8- cDCs. The pre-cDCs, which comprised 0.05% of splenocytes, expressed a CD11c(int) CD45RA(lo) CD43(int) SIRP-alpha(int) CD4- CD8- major histocompatibility complex class II-negative surface phenotype. The pre-cDCs were not monocytes. Monocytes generated few cDCs in steady-state recipient mice. However, when transferred into mice with an inflammatory milieu dependent on granulocyte-macrophage colony-stimulating factor, monocytes produced a distinct type of splenic DC. Thus, the inflammatory status of the host influences the developmental origin and type of DC present in lymphoid tissues.
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PMID:Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. 1668 Jan 43

Because of their unsurpassed potency in presenting antigens to naive T cells, dendritic cells are considered to be an important candidate in the development of immunotherapeutic strategies. Despite the high potential of dendritic cell-based immunotherapy, as a so-called dendritic cell vaccination, few clinical approaches using dendritic cell vaccination have been performed in the dog because of very limited information regarding the generation of canine dendritic cells and their functional properties. We therefore established a protocol for the efficient generation of dendritic cells from canine bone marrow cells using recombinant feline granulocyte-macrophage colony-stimulating factor and canine interleukin-4. Dendritic cells were generated efficiently: a yield of 1-9 x 10(6) cells per approximately 0.5 ml of canine bone marrow aspiration was achieved. These dendritic cells showed features shared with mouse and human dendritic cells: dendrite morphology, expression of surface markers MHC class II and CD11c, and up-regulation of molecules related to antigen presentation (MHC class II, B7-1, and B7-2) by activation with lipopolysaccharide. Moreover, the dendritic cells demonstrated phagocytic activity, processing activity of pinocytosed proteins, and activation of allogeneic T cells far more potent than that by macrophages. Our findings suggest that the bone marrow-derived dendritic cells are functional for the capturing and processing of antigens and the initiation of T cell responses.
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PMID:Efficient generation of canine bone marrow-derived dendritic cells. 1695 80

Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models. To address this controversy, we used several modes of T lymphocyte activation in osteoclast differentiation--mitogen-pulse, anti-CD3/CD28 stimulation and in vivo and in vitro alloactivation. Osteoclast-like cells were generated from non-adherent immature haematopoietic monocyte/macrophage progenitors in murine bone-marrow in the presence of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) and monocyte-macrophage colony-stimulating factor (M-CSF). All modes of in vivo and in vitro T lymphocyte activation and both CD4(+) and CD8(+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell (DC) differentiation. Osteoclast-inhibitory effect was associated with T lymphocyte activation and not proliferation, and could be replaced by their culture supernatants. The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis, because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts. Inhibition was associated specifically with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down-regulated RANK, CD115, c-Fos and calcitonin receptor expression, and increased differentiation towards CD11c-positive DC. An activated T lymphocyte inhibitory role in osteoclastogenesis, confirmed in vitro and in vivo, mediated through GM-CSF release, may be used to counteract activated bone resorption mediated by T lymphocyte-derived cytokines in inflammatory and immune disorders. We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis, thereby confirming the functional link between alloreaction and bone metabolism.
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PMID:Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down-regulation of receptor activator of nuclear factor-kappaB and c-Fos. 1696 9

Liver transplant tolerance in pigs, rats, and mice has been disclosed for decades, but the underlying mechanisms are not completely understood. Accumulating data indicate that residing dendritic cells (DC) are important in determining direction of immune responses in the liver. However, our knowledge remains very limited due to the difficulties in obtaining sufficient liver DC. Most of the previous studies were dependent on DC propagated in vitro with growth factors and cytokines. In this study, we adopted an approach to transfect genes into the mouse liver by tail vein injection of plasmid DNA. Transfection with plasmid granulocyte-macrophage colony-stimulating factor markedly expanded liver CD11c(+) DC mainly located in portal regions, while liver B220(+) DC were dramatically generated after injection with plasmid interleukin (IL)-3/CD40L largely present in the lobules. Although both were phenotypically mature and strong T-cell stimulators, CD11c(+)DC induced potent T-cell response while B220(+)DC induced T-cell hyporesponsiveness. Administration of CD11c(+)DC accelerated cardiac allograft rejection, while B220(+)DC significantly prolonged graft survival. This hyporesponsiveness is not due to inhibition of DC/T-cell interaction, but rather through an active process of stimulating T-cell apoptosis. Compared to B220(+) DC that expressed messenger RNA of (TLR) 1, 2, 6, 7, and 9, CD11c(+)DC expressed all TLR 1 to 9. TLR 9 ligation stimulated very high IL-12 in CD11c(+) DC, but high IL-10 and no IL-12 in B220(+) DC. In conclusion, through these mechanisms, liver DC may be actively involved in immune regulation in the liver.
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PMID:In vivo expansion of two distinct dendritic cells in mouse livers and its impact on liver immune regulation. 1713 87

Two subsets of sheep afferent lymph dendritic cells (DC) are defined by the differential expression of CD172a and CD45RA. The majority (~70%) of CD172a(+) subset is CD45RA/CD11c(+)/CD207(+)/TLR4(+). The CD172a(-) DC are CD45RA(+)/CD207(-) and express low levels of CD11c and CD86. Real-time RT-PCR showed that CD172(+) DC produce IL-1beta and IL-10 and high levels of IL-18 but almost no IL-12p40; CD172a(-) DC express IL-12p40 but no IL-10 and low levels of IL-1beta and IL-18. Gene gun-delivered granulocyte-macrophage colony-stimulating factor (pGM-CSF) caused an early rise in the output of CD172a(+) DC, changes to DC phenotype and significant increases in the levels of expression cytokine transcripts. However, pGM-CSF did not affect any qualitative changes to cytokine expression, CD172a(+) DC remained IL-10(+)/IL-12p40(-) and the CD172(-) DC remained IL-10(-)/IL-12p40(+).
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PMID:Gene gun-delivered pGM-CSF adjuvant induces enhanced emigration of two dendritic cell subsets from the skin. 1730 76

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful immune-stimulating factor that helps to generate a systemic, strong, and long-lasting immune response. However, whether the transduction of GM-CSF to tumor cell results in tumor regression and optimizes local immune microenvironment remains to be investigated. In this study, using an experimental murine tumor model, we demonstrated that the in vivo growth of 3LL tumor cells modified with the GM-CSF gene (3LL-GM) was inhibited even when the tumor diameter was over 7 mm (big tumor), and mice inoculated with GM-CSF gene-modified 3LL cells survived over 90 days, whereas mice inoculated with control parental 3LL cells and 3LL cells transduced with control vector all succumbed to the tumor by day 17 after tumor inoculation. Further analysis showed that targeted expression of GM-CSF in 3LL tumor cells markedly enhanced the systemic antitumor effect, including specific lymphocytes proliferation, cytotoxicity against 3LL tumor, and increased production of IFN-gamma. GM-CSF gene-modified 3LL cells significantly protected the mice from the parental 3LL tumor challenge. More importantly, the percentage of dendritic cells (DCs) in tumor site was greatly increased and the DCs differentiated into CD11c(+)CD8alpha(+) cells, which were reported to be able to benefit the induction of CD8(+) cytotoxic T lymphocytes (CTLs) that contribute to tumor regression. Our research indicated that GM-CSF could optimize the immune microenvironment in the tumor site, which provides a potent approach for immunotherapy of tumors.
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PMID:Big tumor regression induced by GM-CSF gene-modified 3LL tumor cells via facilitating DC maturation and deviation toward CD11c+CD8alpha+ subset. 1776 May 59

Human in vitro generated dendritic cells and the exosomes they release are potential tools for the modulation of immune responses. Here, we characterized differently generated monocyte-derived dendritic cells (MDDCs) and their exosomes. Culturing of peripheral CD14+ cells from the same individuals with either interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (conventional MDDCs) or alternatively with IL-4 and IL-3 generated immature MDDCs in 7 days. Fluorescence-activated cell sorting (FACS) analysis showed that the IL-4/IL-3-generated MDDCs had significantly lower percentages of CD1a+, CD40+ and CD80+ cells and a higher percentage of CD86+ cells as compared with conventional MDDCs. In addition, IL-4/IL-3-generated MDDCs had significantly higher densities of major histocompatibility complex (MHC) class I [human leucocyte antigen (HLA)-ABC], MHC class II (HLA-DR), CD11c and the tetraspanin CD81 as compared with conventional MDDCs. In a comparison of their ability to stimulate CD8+ T cells, we found that the IL-4/IL-3 MDDCs were slightly more efficient than the conventional MDDCs at inducing interferon (IFN)-gamma release in response to viral peptides. Exosome morphology was confirmed by electron microscopy and exosome phenotypes were analysed by flow cytometry and western blot. In comparison to exosomes from conventional MDDCs, exosomes from IL-4/IL-3-generated MDDCs showed significantly stronger signals for HLA-ABC, HLA-DR, CD11c, CD63 and CD81. Thus, phenotypically the exosomes largely reflected their MDDCs of origin. When exosomes were loaded with viral peptides, both types of exosomes induced IFN-gamma release from CD8+ T cells. Our findings might have significance for the development of DC- and exosome-based therapies.
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PMID:Different types of in vitro generated human monocyte-derived dendritic cells release exosomes with distinct phenotypes. 1794 17

Human monocyte-derived dendritic cells (DCs), stimulated with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 1 week, major histocompatibility complex killed human tumor cells in 24-hour cytotoxicity assays. These immature DCs were >90% CD11c, major histocompatibility complex class II(+), but <1% were CD83(+) cells. Within 24 hours, these DCs ingested tumor membranes. The DC cells also lysed Jurkat lymphoma cells, but not Jurkat cells genetically knocked out of the Fas-associated death domain (FADD) or caspase-8. DC2.4, a cloned murine DC line, also displayed cytotoxicity toward U-251 cells, although these murine DCs were less potent than human DC. DC2.4 did not kill Jurkat cells, rat T9 glioma cells, or human Caco-2 colon cancer cells, suggesting that a unique receptor or ligand interaction exists between the DC and U-251 cells. This interaction was destroyed by the paraformaldehyde fixation of the tumor cells. Supernatants from the cultures of DC2.4 and tumor cells were analyzed by the Griess reaction for signs of nitric oxide (NO) production. Augmented NO production occurred in DC2.4/U-251 and DC2.4/Jurkat cultures but was not seen in the human DC/U-251 cultures. These studies suggest that DCs possess different mechanisms of tumoricidal activity.
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PMID:Human allogeneic and murine xenogeneic dendritic cells are cytotoxic to human tumor cells via two distinct pathways. 1797 70

The mechanism(s) by which herpes simplex virus type 1 (HSV-1) latency is established in neurons is not known. In this study, we examined the effect of dendritic cells (DCs) on the level of HSV-1 latency in trigeminal ganglia (TGs) of ocularly infected BALB/c and C57BL/6 mice. We found that immunization of wild-type mice with FMS-like tyrosine kinase 3 ligand (Flt3L) DNA, which increases the number of DCs, increased the amount of latency in infected mice. Conversely, depletion of DCs was associated with reduced latency. Latency was also significantly reduced in Flt3L(-/-) and CD8(-/-) mice. Interestingly, immunization of Flt3L(-/-) but not CD8(-/-) mice with Flt3L DNA increased latency. Transfer experiments using DCs expanded ex vivo with Flt3L or granulocyte-macrophage colony-stimulating factor suggested that increased latency was associated with the presence of lymphoid-related (CD11c(+) CD8alpha(+)) DCs, while reduced latency was associated with myeloid-related (CD11c(+) CD8alpha(-)) DCs. Modulation of DC numbers by Flt3L DNA immunization or depletion did not alter acute virus replication in the eye or TG or eye disease in ocularly infected mice. Our results suggest that CD11c(+) CD8alpha(+) DCs directly or indirectly increase the amount of HSV-1 latency in mouse TGs.
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PMID:Lymphoid-related CD11c+ CD8alpha+ dendritic cells are involved in enhancing herpes simplex virus type 1 latency. 1866 91


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