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 CMK cell line is an acute megakaryoblastic leukemia cell line established from a patient with Down's syndrome, and is known to possess characteristics of normal megakaryocytes. Several cytokines with the ability to stimulate megakaryopoiesis, such as interleukin-3 (IL-3), interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulated colony formation by CMK cells. The present study revealed that tumor necrosis factor-alpha (TNF-alpha) stimulated colony formation by CMK cells; the potency was almost equal to that of IL-3, IL-6 or GM-CSF. Scatchard plot analysis revealed that CMK cells possess two types of specific binding sites for TNF-alpha. The high-affinity binding sites had an affinity constant of 0.18 nM, and numbered 5,000. The low-affinity binding sites had an affinity constant of 1.8 nM and numbered 19,000. These results raise the possibility that TNF-alpha can act as a growth-stimulating agent on megakaryocyte-lineage cell line.
Jpn J Cancer Res 1992 Sep
PMID:Tumor necrosis factor-alpha stimulates colony formation by a megakaryoblastic leukemia cell line, CMK. 142 11

Tumor-bearing host (TBH) macrophages (M phi) suppress T cell alloresponses, and this study suggests granulocyte-macrophage colony-stimulating factor (GM-CSF), a molecule associated with suppressive M phi activity during tumor growth, signals more immunosuppression. In the absence of M phi, GM-CSF increased T cell proliferation in response to alloantigen. However, TBH M phi-mediated suppression of allorecogntion was further induced by GM-CSF. Allogeneic mixed lymphocyte reaction (MLR) cultures, containing normal host (NH) M phi, were either unaffected or enhanced. Prostaglandin E2 (PGE2), a highly suppressive monokine that decreases alloreactivity, did not seem to be involved in the suppression caused by the TBH M phi/GM-CSF interaction. M phi-CSF (M-CSF) addition to cultures did not reverse the suppression caused by TBH M phi and GM-CSF, and inhibition of PGE2 synthesis did not change the response to M-CSF. TBH Ia- M phi, a suppressor population that predominates among splenic M phi during tumor growth, demonstrated significantly lower reactivity in the presence of GM-CSF. In contrast, alloresponses suppressed by NH Ia- M phi demonstrated higher reactivity in the presence of GM-CSF. The data collectively suggest that TBH M phi respond differently to GM-CSF, and that tumor-induced changes in GM-CSF responsiveness affect M phi accessory ability.
Immunobiology 1992 Sep
PMID:Tumor growth changes the contribution of granulocyte-macrophage colony-stimulating factor during macrophage-mediated suppression of allorecognition. 145 14

We have studied the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the infectivity of promastigotes of Leishmania amazonensis, an obligate intramacrophage parasite. We measured the capacity of the promastigotes to infect macrophages after preincubation at different temperatures (28, 34, and 37 degrees C) with recombinant murine GM-CSF, as well as the effect of an anti-murine GM-CSF antibody on the in vitro and in vivo infectivity of the parasite. GM-CSF increases the capacity of the promastigotes to infect cells when preincubated at 34 and 37 degrees C, whereas the anti-GM-CSF antibody exerts the opposite effect: it decreases the internalization rate and the progression of infection in macrophage cultures and slows the growth of the lesion in infected BALB/c mice. Neither of the described effects were observed when the in vitro and in vivo infections were made with amastigotes. Promastigotes die in a time-dependent manner when incubated at temperatures higher than 28 degrees C in the absence of GM-CSF. They are protected from this heat-induced death by incubation with the recombinant hormone. Our interpretation of these data is that the increase in the infectivity of promastigotes when incubated with GM-CSF at the temperatures at which infection occurs (34 and 37 degrees C) is due to the larger number of surviving forms within the infecting population. The decrease in infectivity when they are incubated with the antibody is due to inhibition of the protection conferred by the GM-CSF produced by the macrophages during the in vitro and in vivo infections.
Infect Immun 1992 Sep
PMID:Granulocyte-macrophage colony-stimulating factor increases the infectivity of Leishmania amazonensis by protecting promastigotes from heat-induced death. 150 Jan 59

Monocytes are important accessory cells in the activation of T cells for specific antigen recognition yet little is known of their regulation. We demonstrated here that interleukin-2 (IL-2)-induced human lymphokine-activated killer (LAK) cells can inhibit monocyte antigen presentation, depending on the state of differentiation of the monocytes. Adherent monocytes cultured for 4 days in medium or granulocyte-macrophage colony-stimulating factor (GM-CSF) were found to equally process and present intact Candida albicans to autologous Percoll gradient-isolated T cells, as measured by [3H]thymidine uptake. However, only the GM-CSF-cultured monocytes were functionally inhibited by autologous 4-day IL-2-induced LAK cells. Even soluble candidal cell wall mannoprotein antigens could not be presented by these monocytes after exposure to LAK cells. Pretreatment of these monocytes with LAK cells for 1 h, followed by subsequent removal of the nonadherent LAK cells, was sufficient to cause significant inhibition, with maximal inhibition observed after 4 h. Northern (RNA) blot analysis indicated that mRNA expression for IL-1 alpha and IL-1 beta in response to C. albicans stimulation was also down-regulated in GM-CSF-cultured monocytes exposed to LAK cells. Interestingly, freshly isolated, Percoll gradient-purified large granular lymphocytes did not suppress antigen presentation in GM-CSF-treated monocytes. Another important finding was the inability of LAK cells to suppress the ability of freshly isolated or gamma interferon-cultured monocytes, which are resistant to LAK cell-mediated lysis, to present antigen to T cells. In contrast, IL-3 was similar to GM-CSF in inducing LAK cell susceptibility in monocytes. Taken together, these results indicated that IL-2 can induce LAK cells to down-regulate antigen presentation function in a select set of monocytes that have been activated by colony-stimulating factor (GM-CSF and IL-3) but not by gamma interferon. LAK cells may therefore play an important role in regulation of monocytes and their function, depending on their differentiation state.
Infect Immun 1992 Sep
PMID:Lymphokine-activated killer cell regulation of T-cell-mediated immunity to Candida albicans. 150 Jan 66

Children with human immunodeficiency virus (HIV) infection have impaired polymorphonuclear leukocyte (PMNL) function leading to secondary bacterial infections and possible acceleration of underlying viral disease. The chief antiviral defense mechanism of PMNL is antibody-dependent cellular cytotoxicity (ADCC). Accordingly, the ADCC of PMNL and mononuclear cells from HIV-positive children was compared with that of HIV-positive adults, healthy adults, and age-matched healthy children. PMNL and mononuclear cells from HIV-positive children incubated with hyperimmune HIV immune globulin (HIVIG) gave significantly lower ADCC compared with PMNL or mononuclear cells of healthy age-matched children incubated with HIVIG (P less than .05). The ADCC of mononuclear cells of healthy adults in the presence of plasma from HIV-infected children was significantly less than that of the same cells in the presence of plasma from HIV-positive symptomatic or asymptomatic adults. Augmentation of ADCC of the PMNL from HIV-positive children with interferon-gamma or granulocyte-macrophage colony-stimulating factor did not occur. Thus, the defect in ADCC of HIV-positive children is due to defects of both effector cells and antibody function.
J Infect Dis 1992 Sep
PMID:Deficient polymorphonuclear cell and mononuclear cell antibody-dependent cellular cytotoxicity in pediatric and adult human immunodeficiency virus infection. 150 Jul 35

Human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia and also a neurological disease, tropical spastic paraparesis. Tax protein (p40tax) of HTLV-1 activates in trans its own transcriptional enhancer in the long terminal repeat and also those in some cellular genes such as interleukin 2 receptor alpha, granulocyte-macrophage colony-stimulating factor, Fos, Jun and MHC class I. Thus, Tax has been proposed to play a critical role in the pathogenesis induced by HTLV-1 infection. Here, we report formation of a complex of Tax protein with the precursor protein p105 of the NF-kappa B p50 subunit. p105 was co-immunoprecipitated with Tax protein from cells infected with HTLV-1 from cells transfected with the Tax expression plasmid, but not from cells transfected with inactive mutants of Tax. Furthermore, a GST-p105 fusion protein produced in Escherichia coli bound to Tax protein. These results strongly suggest that the trans-activator Tax protein forms a complex with precursor NF-kappa B p105 and plays a role in trans-activation of transcriptional initiation.
Oncogene 1992 Sep
PMID:Transcriptional activator Tax of HTLV-1 binds to the NF-kappa B precursor p105. 150 85

Although the action of insulin-like growth factor-I (IGF-I) on bone formation has been extensively investigated, the effect of the factor on bone resorption is little known. We first examined the effect of IGF-I on bone resorption by preexistent osteoclasts by using unfractionated bone cells cultured on dentin slices. IGF-I had a dose-related effect of stimulating bone resorption by preexistent osteoclasts, whereas IGF-II did not. When IGF-I was added to cultures of bone cells after preexistent osteoclasts had degenerated on the dentin slices, IGF-I increased the number of osteoclastic multinucleate cells (MNCs) with tartrate-resistant acid phosphatase activity. Moreover, IGF-I augmented the area of pits produced by newly formed osteoclasts. These results suggest that IGF-I directly or indirectly stimulates osteoclast recruitment and activation. Therefore, we next examined the direct effect of IGF-I on osteoclastic MNC formation by using hemopoietic blast cells. In the presence of 1,25-dihydroxyvitamin D3, IGF-I, like granulocyte-macrophage colony-stimulating factor (GM-CSF), dose-dependently increased the number of TRAP-positive MNCs. This stimulatory effect of IGF-I was additive with that of GM-CSF. Both IGF-I and GM-CSF supported the survival of the blast cells, indicating that IGF-I as well as GM-CSF are supporting factors for osteoclast differentiation. In addition, the blast cells possessed high affinity binding sites for IGF-I, with a Kd of 0.8 nM. These data, thus, indicate that IGF-I stimulates osteoclastic bone resorption through its direct or indirect action of supporting the generation and activation of osteoclasts.
Endocrinology 1992 Sep
PMID:Insulin-like growth factor-I supports formation and activation of osteoclasts. 150 51

Polyethylene glycol (PEG) modification improves the pharmacological properties of proteins, usually extending plasma half-life and concomitantly increasing in vivo bioactivity, reducing both antigenicity and immunogenicity, and increasing solubility and resistance to proteolysis. Despite these established benefits, few PEG proteins are in use. Current coupling methods are either traumatic for the protein or involve lengthy and difficult procedures to activate monomethoxyPEG (MPEG). We have applied a new coupling method that allows coupling of MPEG directly to proteins under physiological conditions. Using this method with recombinant human (rh)granulocyte-macrophage colony-stimulating factor (GM-CSF) we were able to construct biologically active PEG-GM-CSF. Fast protein liquid chromatography (FPLC) and phase-partitioning confirmed the presence of PEG modification, and the former was used to fractionate modified and unmodified material. Bioactivity was measured in colony assays of normal human bone marrow cells and by tritiated thymidine uptake (of chronic myeloid leukemia cells and TF-1 cells). With both uptake and colony assays, using unfractionated material, we observed only a modest reduction in biological activity. Assays of FPLC-fractionated material confirmed that much of the bioactivity of the PEG-GM-CSF preparations was due to the modified species and any residual unmodified GM-CSF. Species uncontaminated by tresylmonomethoxyPEG (TMPEG; which was somewhat inhibitory in the thymidine uptake assay and eluted over a broad region of the FPLC profile) had no significant reduction in activity, but we cannot rule out the possibility that PEG-GM-CSF species eluting elsewhere in the profile had modest reduction of activity. Subcutaneous injection into mice confirmed the anticipated improved half-life in vivo and demonstrated a longer uptake from the injection site. This is, as far as we are aware, the first successful construction of PEG-GM-CSF with conserved biological activity.
Exp Hematol 1992 Sep
PMID:Polyethylene glycol (PEG)-modified granulocyte-macrophage colony-stimulating factor (GM-CSF) with conserved biological activity. 150 37

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) produces dose-related therapeutic and toxic effects; however, relationships between its pharmacokinetics and pharmacodynamics have not been extensively evaluated. The following studies were undertaken to investigate patterns in the disposition of rHuGM-CSF administered after high-dose chemotherapy (cyclophosphamide, cisplatin, carmustine) and autologous bone marrow support. Continuous 14 or 21 day intravenous infusions or daily 4-hour infusions were studied at doses of 1.2 to 19.2 micrograms/kg/d. GM-CSF was measured by an enzyme-linked immunosorbent assay from serum and urine samples collected throughout drug administration. Pharmacokinetic parameters were determined by compartmental (4-hour infusions) or noncompartmental methods (continuous infusions). GM-CSF was rapidly eliminated from the serum. Average systemic exposure increased with dose, although wide interpatient variability was evident. Approximately one half of the patients receiving continuous infusions demonstrated increasing GM-CSF clearance that corresponded to the appearance of white blood cells in the periphery. Conversely, clearance decreased in those experiencing renal dysfunction during the infusion. The percentage of a GM-CSF dose found in 24-hour urine collections was substantially reduced in the latter group. A subset of patients who developed renal dysfunction also experienced significant hypotension. Rapidly increasing serum GM-CSF concentrations corresponded to the hypotensive episodes. GM-CSF serum concentration monitoring may be useful for evaluation of therapeutic and toxic effects in patients receiving high-dose chemotherapy with autologous bone marrow support.
Blood 1992 Sep 01
PMID:Disposition of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving high-dose chemotherapy and autologous bone marrow support. 151 35

The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double-blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM-CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.
Blood 1992 Sep 01
PMID:Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial. 151 37


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