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)

The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-gamma). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II-expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-gamma, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-gamma under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-gamma.
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PMID:Activation of human T cells by major histocompatability complex class II expressing neutrophils: proliferation in the presence of superantigen, but not tetanus toxoid. 916 55

A murine model of pneumonia due to the mouse pneumonitis agent (MoPn [murine Chlamydia trachomatis]) in mice deficient in CD4+ T-cell function (major histocompatibility complex [MHC] class II function [class II-/-], CD8+ T-cell function (beta2-microglobulin deficient, MHC class I deficient [Beta2m-/-]), B-cell function (C57BL/10J-Igh(tm1Cgn) [Igh-/-]), and gamma interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [Ifg-/-]) or interleukin-4 (C57BL/6J(tm1Cgn29) [IL4-/-]) production was employed to determine if each of these mechanisms was critical to resistance against reinfection by C. trachomatis or if alternate compensatory mechanisms existed in their absence which could potentially be exploited in vaccine development. Resistance to reinfection with MoPn was heavily dependent on CD4+ T cells. CD4 T-cell-deficient MHC class II-/- mice were very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked antibody production but did produce IFN-gamma, apparently by mechanisms involving NK and CD8+ T cells. Neutralization of IFN-gamma in these mice led to a borderline increase in susceptibility, showing a possible role (albeit small) of this cytokine in this setting. Tumor necrosis factor alpha (TNF-alpha) was also present at increased levels in these mice. Igh-/- B-cell-deficient mice which produce no antibody to MoPn were only modestly more susceptible to reinfection than immunized B-cell-intact controls, showing that antibody, including lung immunoglobulin A, is not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were elevated in Igh-/- mice compared to those in controls. IL-4-/- mice (deficient in Th2 function) could develop normal resistance to reinfection with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impaired in their ability to develop acquired immunity to MoPn, again indicating a role for this cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg-/- mice (which have elevated levels of other cytokines, including TNF-alpha and granulocyte-macrophage colony-stimulating factor) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma is not an absolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depletion of TNF-alpha significantly increased MoPn levels in the lungs in these mice. Thus, resistance to reinfection in this model is flexible and multifactorial and is heavily dependent on CD4+ T cells, with a probable role for IFN-gamma and TNF-alpha and a possible modest role for Th1-dependent antibody. Since IFN-gamma was dispensable in host defense, the highly effective mechanism or mechanisms which can compensate for its absence (which include TNF-alpha) deserve further study.
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PMID:Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis. 919 62

Invariant chain (Ii) plays an important role in major histocompatibility complex (MHC) class II antigen processing and presentation and is constitutively synthesized in B lymphocytes, in macrophages, dendritic cells and in some epithelial cells. It has been shown that interferon-gamma, tumour necrosis factor-alpha and interleukin-4 co-regulate Ii and MHC class II expression in various cell types. We describe here a novel regulation of Ii expression in macrophages. Treatment of the premature monocytic cell lines WEHI 265.1, M1 and WEHI-3B with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) strongly enhances Ii expression while class II expression is not induced. In contrast, GM-CSF did not enhance Ii in mature macrophage cell lines. The increase of Ii expression in WEHI 265.1 cells takes several days. This long induction time, and a difference in activity between GM-CSF-conditioned medium and GM-CSF, together suggest that GM-CSF stimulates WEHI 265.1 cells to secrete a factor that modulates Ii expression. These results may imply a class II-independent function of Ii, which we discuss in this paper.
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PMID:Granulocyte-macrophage colony-stimulating factor elevates invariant chain expression in immature myelomonocytic cell lines. 920 74

In mouse Peyer's patches (PP), dendritic cells (DC) are localized in T cell areas as NLDC145+ CD11c+ cells, and in the dome and corona region of the follicle as NLDC145- CD11c+ cells, respectively, suggesting the presence of two different DC populations with distinct roles in antigen uptake, processing, and presentation. However, it is not clear how this relates to DC maturation. In this report, we demonstrate that freshly-isolated CD11c+ DC have the properties of immature DC since they endocytose soluble antigens, phagocytose particulate material such as latex beads, synthetize major histocompatibility complex (MHC) class II and invariant chain, but, at the same time, display low stimulatory activity for resting T cells, as shown in mixed-lymphocyte reaction and oxidative mitogenesis assays. When cultured for 24 h in the presence of the cytokines granulocyte-macrophage colony-stimulating factor and tumor necrosis factor or anti-CD40, the cells undergo dramatic phenotypic and functional changes characteristic of DC maturation. After 24 h stimulation in vitro, CD11c+ cells lose the ability to take up proteins such as ovalbumin, and in parallel with this decline, the biosynthesis of MHC class II and invariant chain is dramatically down-regulated or eliminated. On the other hand cells treated in vitro exhibit on the cell surface higher levels of MHC class II, of co-stimulatory molecules (CD80, CD86), of adhesion molecules (CD44, intercellular adhesion molecule-1), and acquire expression of the interdigitating DC surface marker NLDC145. Concomitantly, the ability to stimulate naive T cells drastically increased after in vitro treatment with both stimuli. Taken together, our results indicate that the majority of DC in the PP are immature in terms of their antigen-uptake capacity. These sentinel antigen presenting cells are strategically positioned at the dome region of PP, where antigens are transcytosed via the M cells from the gut lumen. A second population of mature interdigitating NLDC145+ CD11c+ DC stimulates naive unprimed T cells in interfollicular areas by up-regulation of surface ligands and accessory signals.
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PMID:Maturation of Peyer's patch dendritic cells in vitro upon stimulation via cytokines or CD40 triggering. 920 80

Dendritic cells (DC) have been generated in vitro from either CD34+ haemopoietic progenitor cells (HPC) or peripheral blood monocytes (Mo) in the presence of specific cytokine combinations, including granulocyte-macrophage colony-stimulating factor (GM-CSF). Since differences between DC from either source may be important for the clinical use of these antigen-presenting cells (APC), a comparative analysis was performed. HPC were expanded in the presence of interleukin (IL)-3, IL-6 and stem cell factor (SCF) (days 1-7) and subsequently induced by IL-4+ GM-CSF (days 8-26) to differentiate to Langerhans-type cells (pLC). The latter cytokines were similarly used to generate Mo-derived LC (mLC). Maturation of both cell types, pLC and mLC, to interdigitating DC-type cells (iDC) was induced by tumour necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS). Analysis of mLC/pLC and miDC/piDC with respect to morphology, phenotype, antigen uptake and presentation revealed a high similarity of DC from either source. The majority of mLC, however, exhibited a more mature differentiation stage, compared to pLC, evidenced from lower numbers of multilaminar MHC class II compartments and less efficient APC function for extracellular protein antigens. Although macropinocytosis was performed by LC, neither LC nor iDC from either source were able to take up > or = 0.5 microm latex beads. However, phagocytosis of 0.5 microm and 1 microm beads was performed by Mo that could subsequently be induced to become iDC, thus providing the unique opportunity to present phagocytosed material in DC-type fashion. Mo may be the preferential source for clinical use of iDC-type cells since preparation and culture are easier to perform and are less costly while APC function is similar to HPC-derived iDC.
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PMID:CD34+ peripheral blood progenitor cell and monocyte derived dendritic cells: a comparative analysis. 940 Oct 55

Human monocytes cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-13 for 7 days differentiate into cells with the morphology and function of dendritic cells (DC). We have investigated the effect of IL-10 on this differentiation pathway. In the presence of IL-10 cells did not develop DC morphology, did not express CD1a and had lower levels of MHC class II. IL-10 promoted the differentiation of large cells with the morphology, cytochemistry and membrane phenotype of macrophages, including staining for nonspecific esterase and high levels of CD14, CD16 and CD68. The effect of IL-10 was dose dependent and was best appreciated when the cytokine was added at the initiation of the culture, as addition on day 3 was less inhibitory. When added to already differentiated DC on day 6, IL-10 caused only a modest reduction of MHC class II and CD1a expression, and no acquisition of the macrophage markers CD14, CD16 and CD68. Prolonged incubation up to 5 days with IL-10 did not induce a shift of differentiated DC to macrophages. On the other hand, the macrophages obtained by culturing for 7 days with GM-CSF+IL-13+IL-10 did not shift to DC upon removal of IL-10 for up to 3 days. Thus, the effect of IL-10 on monocyte differentiation, occurs only at the precursor level and confers an irreversible phenotype. From a functional point of view, cells cultured in the presence of IL-10 were poor stimulators of allogeneic cord blood T cells in mixed lymphocyte reaction (MLR) and presented tetanus toxin (TT) to specific T cell lines with much less efficiency than control DC. In contrast, IL-10-cultured DC showed 7 times greater endocytosis of FITC-dextran. This increased endocytosis was mostly mediated via the mannose receptor, as demonstrated by blocking with unlabeled mannose. In conclusion, IL-10 inhibits DC differentiation from monocytes and, in a substantial proportion of the cells, promotes the differentiation to mature macrophages. Intriguingly, IL-10 inhibits antigen presentation while it stimulates endocytic activity.
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PMID:IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. 948 15

Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-gamma/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I-restricted type I T-cell response.
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PMID:Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses. 951 46

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

We have previously shown that mouse bone marrow-derived mast cells (BMMC) can process and present immunogenic peptides to CD4 T cells. Here, we report on a T cell-dependent MHC class II-mediated mast cell activation resulting in IL-4 transcription and protein release. Presentation of optimal doses of ovalbumin peptide 323-339 resulted in IL-2 production by a specific T cell hybridoma and increase in IL-4 mRNA transcription in mast cells. IL-4 mRNA transcription increased by 200-fold in mast cells treated in IL-3/IL-4/granulocyte-macrophage colony-stimulating factor (high presenters) whereas only a tenfold increase or no increase were obtained with IL-3/IL-4/IFN-gamma- or IL-3-treated mast cells (low presenters), respectively. Induction of IL-4 mRNA transcription in purified mast cells by direct ligation of MHC class II molecules, using anti-I-A and anti-I-E-coated beads, indicates that MHC class II molecules are critical in this signaling pathway. However, when compared to T cells, anti-MHC class II-coated beads were less efficient, indicating a potential role of accessory molecules in this mast cell activation process. IgE-independent IL-4 production by mast cells as a result of cognate interaction with CD4 T cells could be critical for the development of type 2 responses. This novel mechanism may contribute to the induction and/or amplification of specific IgE-mediated allergic responses.
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PMID:IL-4 mRNA transcription is induced in mouse bone marrow-derived mast cells through an MHC class II-dependent signaling pathway. 954 79

Staphylococcal enterotoxin B (SEB) is a superantigen that causes mass proliferation of murine Vbeta8+ T cells via major histocompatibility complex (MHC) class II molecules and leads to their apoptosis or anergy. SEB also stimulates other MHC class II-bearing cells to proliferate and secrete cytokines, some of which might enhance early host defenses against urinary tract infections (UTIs). We investigated the effect of SEB administration on the course of an induced Escherichia coli UTI in mice. Treatment with SEB 3 or 7 days before the infection had no effect on UTI resolution. However, when SEB was administered at the time of infection, bacterial colonization in the bladders was reduced at time points between 6 h and 3 days. This reduction was not due to a physiological effect, such as increased urinary glycosaminoglycans, or altered pH, nor was SEB bactericidal for the inoculum. Cytokine production in the spleens and bladders of SEB-treated and/or infected mice was evaluated by reverse transcription-PCR. SEB treatment resulted in increased levels of interleukin-2 (IL-2), IL-4, IL-6, and IL-10 mRNAs in the spleen and IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha transcripts in the bladder. Also, liver cells from SEB-treated mice expressed IL-6 mRNA, which induces the production of acute-phase proteins. These data indicate that SEB treatment in vivo leads to enhanced UTI resolution through a mechanism that may include direct stimulation of effector cells in the bladder, the action of cytokines induced in the spleen, or cytokine-mediated induction of acute-phase proteins.
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PMID:Treatment of mice with staphylococcal enterotoxin B enhances resolution of an induced Escherichia coli urinary tract infection and stimulates production of proinflammatory cytokines. 987 98


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