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)

Interferon-gamma (IFN-gamma) is a priming agent of polymorphonuclear neutrophilic granulocyte (PMN) oxygen metabolism, and protein kinase C (PKC) is traditionally believed to play a central role in activation of this oxygen metabolism. In the present study, we have shown that the PKC activity in PMN is affected by IFN-gamma. After only 2 minutes exposure to IFN-gamma (100 U/ml), PKC activity was significantly increased in the noncytosolic fraction of the cells. This increase was transient, but toward the end of the priming period of 2 h, the membrane-associated PKC activity increased again to about 152% of control. In the cytosolic fraction, a small and hardly detectable decrease in PKC activity was observed. Treatment of PMN with granulocyte-macrophage colony-stimulating factor (GM-CSF), another PMN priming agent, showed no significant effects on the PKC activity. When the cells were stimulated with the bacterial peptide fMLP after a priming period with IFN-gamma or GM-CSF for 2 h, no significant difference between treated and control cells could be observed. PMN oxygen metabolism, measured by flow cytometry as an accumulation of the fluorescent compound dichlorofluorescein, was in these experiments significantly primed by IFN-gamma, both at baseline and when stimulated with fMLP. The protein kinase C inhibitors H7 and Ro31-8220 blocked the fMLP responses to some extent, but not completely. However, no significant difference between fMLP responses in control and IFN-gamma-treated cells could be detected after administration of inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma affects protein kinase C activity in human neutrophils. 853 5

Fc-gamma receptor III (Fc gamma RIII, CD16) type A is expressed on natural killer cells, on a small subset of peripheral blood monocytes and on mature macrophages. Along with differentiation into macrophages, monocytes will express Fc gamma RIII when cultured with transforming growth factor-beta (TGF-beta). In view of the involvement of granulocyte-macrophage colony-stimulating factor (GM-CSF) in myeloid cell differentiation, we investigated the effect of this cytokine on Fc gamma RIII expression in cultures of peripheral blood monocytes. GM-CSF antagonized TGF-beta-induced expression of Fc gamma RIII on monocytes in vitro in a dose-dependent way. The effect of GM-CSF persisted in cultures until at least day 7. The suppression was at the mRNA level, as shown by Northern analyses with a CD16 specific probe, and the signalling pathway involved tyrosine kinase activity. Interferon-gamma and interleukin-2 had no effect on the induced expression of Fc gamma RIII by TGF-beta, while interleukin-4, similar to GM-CSF, antagonized this induction. Our findings suggest that regulatory cytokine networks can drive monocytes into different effector functions and differentiation pathways.
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PMID:Granulocyte-macrophage colony-stimulating factor antagonizes the transforming growth factor-beta-induced expression of Fc gamma RIII (CD16) on human monocytes. 866 30

Human contact with the nontuberculous mycobacteria (NTM) is quite common, yet serious infections with these organisms were relatively infrequent until the advent of AIDS. Mycobacteria present an important window on the interaction of the innate (neutrophils, macrophages, NK cells) and acquired (T cells and B cells) immune systems. In their attempt to infect macrophages, the mycobacteria use their complex glycopeptidolipid cell wall to down-regulate macrophage responses. Once inside, mycobacteria are subject to the panoply of primary macrophage responses (e.g., vacuolar acidification, lytic enzymes). The infected macrophage produces cytokine signals (e.g., chemokines, interleukin [IL]-12] that recruit and stimulate lymphocytes from the innate (NK cell) and acquired (T and B cells) arms of the immune response to help kill the invading mycobacteria. Lymphocyte products that are central to the activation of macrophages to increased mycobacterial killing include tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The precise mechanisms by which these cytokines work remains unknown. Rare patients who have refractory disseminated NTM infection without HIV infection probably have underlying immune defects in critical pathways for control of mycobacteria. We have recently characterized one such family and found abnormal IL-12 regulation. Interferon-gamma, the cytokine primarily elicited by IL-12, has been used successfully with antimycobacterials for treatment of these patients. The window on the interaction of the innate and acquired immune systems that mycobacteria afford is being opened. Understanding the cell-cell interactions and cytokines involved in NTM infections will lead to new therapeutic approaches.
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PMID:Host defense against nontuberculous mycobacterial infections. 897 76

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

Patients with systemic lupus erythematosus (SLE) were recently shown to be defective in costimulatory molecule CD80 (B7-1) expression on antigen-presenting cells. This study was undertaken to further investigate the expression and cytokine regulation of both CD80 and CD86 (B7-2) on monocytes from patients with SLE. Freshly isolated and in vitro cytokine-stimulated peripheral blood mononuclear cells from 13 patients with SLE and 10 healthy subjects were analysed, cytometrically with dual-fluorescence staining, to detect expression of CD80 and CD86 in the CD14+ monocyte population. The results showed that, as in normal individuals, an overwhelming majority (95.62+/-3.54%) of monocytes from patients with SLE expressed the CD86 molecule, but only a few monocytes (5.54+/-4.36%) had detectable CD80 expression. The effects of interleukin-10 (IL-10) on the expression of CD80 and CD86 on monocytes from patients with SLE and normal controls were similar. IL-10 down-regulated the expression of CD86 while it slightly enhanced that of CD80. Interferon-gamma (IFN-gamma) increased both CD80 and CD86 expression on monocytes from both SLE patients and normal groups, albeit less significantly in the former than in the latter, i.e. CD80: 142.84+/-65.99% versus 226.08+/-78.90%, P<0.05; and CD86: 72.55+/-74.23% versus 153.99+/-94.14%, P<0.05, when expressed as percentage modulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) showed a capacity for up-regulation of CD80 and CD86 expression on monocytes, of a magnitude that was similar both in patients with SLE and in normal subjects. We concluded that CD80 and CD86 were differentially expressed and modulated on monocytes and the defective IFN-gamma-induced up-regulation of CD80 and CD86 expression on SLE monocytes might be a factor in the pathogenesis of SLE.
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PMID:Differential expression and modulation of costimulatory molecules CD80 and CD86 on monocytes from patients with systemic lupus erythematosus. 1002 62

Evidence from several in vitro and animal model studies suggests a modulatory role of haemopoietic, T(H)1 and T(H)2 cytokines in host defence against fungi, and highlights their potential utility as adjunctive therapy for management of systemic mycoses (SM). However, there are limited clinical data to support the use of cytokines in prevention and treatment of SM. Thus, at present no adjunctive treatment is justified for routine use in all patients. Potential application of these immunomodulatory agents include the use of granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor in the management of mycoses in neutropenic patients with myelogenous leukaemia or bone marrow transplantation. Interferon-gamma may have a useful role against aspergillosis in patients with chronic granulomatous disease. Granulocyte colony-stimulating factor-elicited white blood cell transfusions may be life saving to patients with refractory SM. Better understanding of synergy between cytokines and specific antifungals may provide powerful tools for managing these serious infections.
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PMID:Immunotherapy in patients with systemic mycoses: a promising adjunct. 1143 86

A human immunodeficiency virus-infected boy with Scedosporium apiospermum otomastoiditis and a girl with diabetes mellitus and Mucor sinusitis and orbital cellulitis had life-threatening disease progression despite antifungal treatment. Interferon-gamma and granulocyte-macrophage or granulocyte colony-stimulating factor were added, with good functional outcome in both children. Adjunctive therapy with interferon-gamma, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor can be considered for refractory invasive fungal infections.
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PMID:Interferon-gamma and colony-stimulating factors as adjuvant therapy for refractory fungal infections in children. 1529 29

Survivin, a 16.5 kDa tumor associated antigen, is the smallest member of the inhibitor of apoptosis family that is abundantly expressed during development but essentially absent in normal adult tissues. Interestingly, survivin expression is up-regulated in virtually all types of cancers studied, as well as in vascular endothelial cells during tumor associated angiogenesis. Survivin links apoptosis to cell cycle progression and plays a pivotal role in regulation of cell proliferation. These characteristics make survivin a potentially promising generic target for cancer immunotherapy. Hence, a genetic immunization strategy to induce tumor-specific immune responses against human survivin in a pre-clinical animal model was developed. In initial studies, BALB/c mice were immunized by intramuscular injection with DNA coding for human survivin (pcDNA3.1/hSurv). In addition, a construct encoding a secreted version of survivin (pSecTag2B/hSurv) was designed. A plasmid coding for murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was co-injected in both cases as a molecular adjuvant. Expression of survivin following transfection in mouse cells was corroborated. Humoral responses against human survivin were detected in mice sera using two immunization protocols (injections at 2- or 3-week intervals). The humoral response was markedly improved by secretion of survivin and co-expression of GM-CSF. The predominant antibody subclass detected in responsive mice was IgG2a, suggesting that a Th1-CD4+ cellular response had been induced. Furthermore, DNA immunization with survivin encoding vectors generated an effective CD8+ T cell response measured as an increase of cytotoxic Interferon-gamma (IFN-gamma) secreting CD8+ T cells. In conclusion, intramuscular genetic immunization of mice with human survivin encoding plasmids induced a survivin-specific humoral as well as cellular immune response in recipient mice. Secretion of survivin and co-injection of GM-CSF as a genetic adjuvant appear to be more important in generating an humoral than a cellular immune response.
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PMID:Naked DNA immunization as an approach to target the generic tumor antigen survivin induces humoral and cellular immune responses in mice. 1644 67


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