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)

HLA class I and II molecules play a central role in regulating host immune responses against microbial infections because they present foreign antigens to CD8+ and CD4+ T lymphocytes, respectively. Many cytokines, especially interferons (IFN), are known to upregulate human leucocyte antigen (HLA) class I and II gene expression, but the kinetics, expression levels and viral regulation of HLA genes in primary human cells have not been well documented. Stimulation of peripheral blood mononuclear cells (PBMC) with IFN-alpha and IFN-gamma resulted in a 1.5- to twofold increase in HLA class I and beta 2-microglobulin expression in lymphocytes and monocytes. Lymphocytes did not express any detectable HLA class II either basally or after IFN induction. In monocytes, instead, a high basal class II expression was found and it was further induced by IFN-alpha (up to twofold) and especially by IFN-gamma (up to fivefold). In granulocyte-macrophage colony-stimulating factor (GM-CSF) differentiated human macrophages, basal HLA class I and II protein expression levels were high but IFN-gamma stimulation was able to further enhance their expression. Accordingly, class I and II mRNA expression was elevated by IFN-gamma, whereas IFN-alpha practically had no effect on HLA class I mRNA levels. Influenza A virus infection of macrophages resulted in temporary increases in HLA class I, beta 2-microglobulin and class II antigen expression. Neutralization of virus-induced IFN production by antibodies against type I and II IFNs prevented the virus-induced upregulation of HLA antigens. At late times of infection, as analysed by steady-state mRNA expression, both HLA class I and II mRNA were strongly reduced. These results suggest that IFNs are important regulators of HLA genes and responsible for a temporary increase in HLA antigen expression during influenza A virus infection.
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PMID:Regulation of HLA class I and II expression by interferons and influenza A virus in human peripheral blood mononuclear cells. 930 32

The interferon-alpha and -beta (IFN-alpha/beta) producing ability of the two murine dendritic cell (DC) lines D2SC/1 and FSDC was studied. The D2SC/1 cells produced IFN-alpha and -beta when stimulated by herpes simplex virus (HSV), Sendai virus (SV) or by the bacteria Escherichia coli or Staphylococcus aureus Cowan I. Precultivating (priming) D2SC/1 cells with recombinant IFN-beta or a combination of IFN-beta and granulocyte-macrophage colony-stimulating factor increased production of IFN-alpha/beta induced by HSV or the bacteria, but not by SV. Also, the kinetics of IFN-alpha/beta responses were different for SV compared to HSV and the bacteria, suggesting different induction mechanisms. The FSDC cells differed from the D2SC/1 cells mainly in that predominantly IFN-beta was produced, that little or no IFN-alpha/beta production was induced by the bacteria, and that the IFN-alpha/beta responses were most efficiently primed by IFN-gamma. Priming the DC lines with tumour necrosis factor-alpha, interleukin-10 (IL-10) or IL-4 did not affect the IFN-alpha/beta response induced by HSV. The results show that the two DC lines provide a convenient tool to study the induction and control of the IFN-alpha/beta response, as well as the immunoregulatory role of IFN-alpha/beta produced by DC.
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PMID:Production of interferon-alpha/beta by murine dendritic cell lines stimulated by virus and bacteria. 931 10

Intradermal inoculation of mice with naked plasmid DNA encoding the regulatory HIV-1 Nef protein was shown to induce Nef-specific T and B cell responses. Co-inoculation with an expression vector encoding murine granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine known to facilitate the induction of primary immune responses, resulted in a markedly enhanced response to Nef. This was manifested both as an increase in Nef-specific T cell responses and antibody levels. DNA immunization with the Nef and GM-CSF vectors induced primarily a Th1 response as judged by the raised levels of both IFN-gamma and IL-2 from re-stimulated T cells. The immunostimulatory activity of GM-CSF DNA was locally restricted and was observed only if both plasmid vectors were injected at the same site.
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PMID:Amplification of T-cell and antibody responses in DNA-based immunization with HIV-1 Nef by co-injection with a GM-CSF expression vector. 931 20

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

Macrophage-derived interleukin-12 (IL-12) is essential for the activation of a protective immune response against intracellular pathogens. In this study, we examined the regulation of IL-12 mRNA expression by monocyte-derived macrophages (MDM) in response to Mycobacterium bovis BCG stimulation. A reverse transcription-PCR assay detected p40 mRNA of IL-12 at 3 h and showed a peak at 6 to 12 h with a subsequent decline. Semiquantitation of mRNA levels by competitive PCR revealed that pretreatment with gamma interferon (IFN-gamma) amplified the expression approximately 100-fold, while pretreatment with tumor necrosis factor alpha (TNF-alpha) or granulocyte-macrophage colony-stimulating factor augmented this expression about 10-fold. In contrast, pretreatment with IL-10 and IL-4 inhibited IL-12 mRNA expression. These results were further confirmed by measuring the p70 bioactive protein level in each conditioned medium by an enzyme-linked immunosorbent assay. Since IL-12 mRNA expression was weak without cytokine pretreatment and IFN-gamma strongly augmented production, we speculated that IFN-gamma might have a role in BCG stimulation of IL-12 mRNA expression. Unexpectedly, the addition of three different kinds of anti-IFN-gamma antibodies and anti-IFN-gamma receptor antibody and the coaddition of anti-TNF-alpha antibody with anti-IFN-gamma receptor antibody all failed to inhibit IL-12 mRNA expression. However, the MiniMACS method used to remove NK cells from a mononuclear cell suspension inhibited the expression of p40 mRNA but not the expression of mRNA of TNF-alpha or IL-1beta. We concluded that the coexistence of NK cells was essential for the induction of IL-12 in MDM stimulated with BCG rather than through the secretion of IFN-gamma.
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PMID:Interleukin-12 gene expression in human monocyte-derived macrophages stimulated with Mycobacterium bovis BCG: cytokine regulation and effect of NK cells. 935 12

Cytokine-mediated signaling pathways were studied in mouse dendritic cells (DC) by analysis of the activation pattern of STAT factors. Electrophoretic mobility shift assays were performed to detect STAT isoform-specific complexes. Granulocyte-macrophage colony-stimulating factor (GM-CSF) simultaneously induced complexes containing STAT1, STAT3, STAT5A, STAT5B and STAT6. In non-DC, a similar broad activation pattern of STAT factors by GM-CSF or other cytokines has not been observed so far. By comparison, in peritoneal macrophages, GM-CSF induced a complex with the properties of a truncated form of STAT5. Other cytokines tested on DC either failed to induce STAT factors [interleukin (IL)-1 beta, IL-2, IL-15], or activated the same STAT factors as observed in peritoneal macrophages (IL-4, IFN-gamma). Our results implicate a specific effect of GM-CSF on STAT signaling in DC which might account for the cell type-specific effect of this cytokine on development and function.
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PMID:Granulocyte-macrophage colony-stimulating factor induces a unique set of STAT factors in murine dendritic cells. 936 34

The present study investigated the ability of supernatants collected from cultures of healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) to induce, upon brief exposure, tumour-reactive cytotoxic lymphocytes in cancer patients' PBMCs. ACD3S enhanced natural killer (NK) and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. ACD3S contained increased levels of interleukins (IL) 1, 2, 6, 7 and 12, as well as of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). MAbs against these cytokines significantly reduced the ACD3S-induced cytotoxicity. ACD3S-induced cytotoxicity was not inhibited by anti-CD4, CD8 and MHC class I MAbs, but was markedly reduced in the presence of MAb against CD18. In contrast to HD-PBMC, ACD3S derived from cancer patients' lymphocytes exhibited lower levels of the above-mentioned cytokines and exerted reduced biological activity. In conclusion, ACD3S are able to activate, upon short-term incubation, tumour-reactive lymphocytes from cancer patients' PBMCs that lyse a variety of tumour targets, including autologous tumours. ACD3S contain high levels of certain cytokines that positively influence the induction of autologous tumour-reactive lymphocytes. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer. They may also be indicated in the construction of cytokine cocktails that have the ability to induce anti-tumour cytotoxicity.
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PMID:Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes. 937 69

Interleukin-1 (IL-1) is a key player in inflammation and the immune response. To better understand the complex interactions of IL-1 and its receptors in inflammation, we need to investigate how type I and type II IL-1 receptors (IL-1RI and IL-1RII) are regulated by cytokines and other mediators. Using semiquantitative reverse transcriptase PCR and Northern analysis, we examined the regulation of IL-1RI and IL-1RII mRNA levels in bovine polymorphonuclear leukocytes (PMNs) (i.e., neutrophils) and peripheral blood mononuclear cells (PBMCs) in vitro. IL-1RI mRNA levels were up-regulated in PBMCs by recombinant bovine IL-1beta (rBoIL-1beta), recombinant bovine granulocyte-macrophage colony-stimulating factor (rBoGM-CSF), rBoIL-4, recombinant bovine gamma interferon (rBoIFN-gamma), and dexamethasone. IL-1RI mRNA was increased in bovine PMNs exposed to rBoGM-CSF, rBoIL-4, and dexamethasone but was down-regulated by rBoIL-1beta and rBoIFN-gamma. IL-1RII mRNA was increased in bovine PBMCs and PMNs after exposure to rBoIL-1beta, rBoGM-CSF, rBoIL-4, and dexamethasone. In contrast, rBoIFN-gamma down-regulated the expression of bovine IL-1RII mRNA in PBMCs. These findings suggest that the expression of bovine IL-1RI and IL-1RII mRNAs is regulated differently by certain soluble stimuli (e.g., IFN-gamma) in PMNs and PBMCs.
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PMID:Interleukin-1 receptor mRNA expression in activated bovine leukocytes in vitro. 938 5

Pathogenesis of invasive candidiasis may involve regulatory activities of Th2 immunity on phagocytic host defenses. The effects of interleukin (IL)-4 on antifungal capacity of human mononuclear phagocytes against Candida albicans were studied. Incubation of adherent mononuclear leukocytes from healthy donors with IL-4 (1-5 ng ml(-1)) at 37 degrees C for 2-4 days suppressed uptake of C. albicans blastoconidia in the presence of human serum (P < or = 0.01), and anti-IL-4 inhibited its suppressive effect. The effect of IL-4 was protein synthesis-dependent. Interferon-gamma (0.25-25 ng ml(-1)), granulocyte-macrophage colony-stimulating factor (CSF, 20 ng ml(-1)), macrophage-CSF (15 ng ml(-1)) but not IL-10 (100 ng ml(-1)) somewhat counteracted the suppressive effect of IL-4. In contrast, mannose receptor-mediated uptake of blastoconidia in the absence of serum was increased by IL-4. Killing of conidia was decreased after incubation of morphonuclear leukocytes with IL-4 for 2 days (P < 0.05). While superoxide anion production in response to phorbol myristate acetate was decreased by IL-4 (P < 0.05), it was not altered in response to blastoconidia and pseudohyphae. Morphonuclear leukocyte-induced pseudohyphal damage also remained unaltered. These findings suggest that IL-4 plays its detrimental role in invasive candidiasis by predominantly suppressing uptake and killing of blastoconidia by morphonuclear leukocytes. Anti-IL-4, IFN-gamma, GM-CSF and M-CSF appear to counteract suppression of morphonuclear leukocyte phagocytic activity suggesting new approaches to the management of disseminated candidiasis.
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PMID:Interleukin-4 suppresses antifungal activity of human mononuclear phagocytes against Candida albicans in association with decreased uptake of blastoconidia. 939 62

In the present study, we evaluated the in vivo anti-Mycobacterium leprae activities of KRM-1648 (KRM) given at long intervals in combination with ofloxacin (OFLX), clofazimine (CFZ), and dapsone (DDS). We also examined the combined effects of two biological response modifiers (BRMs), gamma interferon (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the therapeutic efficacy of KRM. KRM exhibited potent therapeutic efficacy against M. leprae infection in mice even when given at 4-week intervals. KRM displayed increased efficacy in combination with OFLX, CFZ, and DDS (given three or six times per week) when given to mice in the multidrug combination KRM + OFLX + CFZ + DDS. The therapeutic efficacy of KRM given at 4-week intervals was increased by combined use with IFN-gamma but not by GM-CSF. Adoptive transfer of M. leprae antigen-primed lymphocytes of euthymic mice to recipient athymic nude mice with progressive M. leprae infection markedly enhanced host resistance.
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PMID:Studies on therapeutic activity of benzoxazinorifamycin KRM-1648 in combination with other antimicrobial agents and biological response modifiers interferon-gamma and granulocyte-macrophage colony-stimulating factor against M. leprae infection in athymic nude mice. 940 87


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