Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sera of 25 healthy controls and 75 patients suffering from myelodysplastic syndromes (MDS) were investigated for serum concentration of interleukin-1 alpha (IL-1 alpha), IL-3, IL-6, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), erythropoietin (Epo), and tumor necrosis factor-alpha (TNF-alpha). According to French-American-British (FAB) classification, 21 refractory anemia (RA), seven refractory anemia with ring sideroblasts (RARS), 15 chronic myelomonocytic leukemia (CMML), 12 refractory anemia with excess of blasts (RAEB), and 20 RAEB in transformation (RAEBt) were examined. TNF-alpha levels were inversely correlated with lower levels of hemoglobin concentration (r = -0.31, p = 0.005), irrespective of the requirements for transfusion in anemic MDS patients. Significant differences in TNF-alpha levels between CMML (26.2 +/- 5.9 pg/ml) and the FAB subgroups (16.1 +/- 1.6 pg/ml) were detected. There was an overall inverse relationship between the level of erythropoietin and the degree of anemia, but a wide range of Epo response between patients with similar hemoglobin concentrations. Serum levels of IL-1 alpha and GM-CSF were undetected in most of the patients. In 57% of the samples there were detectable levels of G-CSF, without a correlation of the serum levels with blood cell counts, nor with any of the FAB subcategories. Overall, 29% and 25% of the patient sera exhibited elevated IL-3 and IL-6 levels, respectively. There was no correlation of the serum levels with any of the blood counts, other cytokines, nor FAB subcategories. In conclusion, simple negative feedback mechanism between a specific cytokine and the production of blood cells seems not to be the case in MDS, except for red cell production and erythropoietin concentration. Our data may suggest the involvement of TNF-alpha in the pathogenesis of anemia in MDS.
Leukemia 1992 Dec
PMID:Measurement of serum cytokine levels in patients with myelodysplastic syndromes. 128 Jul 51

Murine BCL-1 B-cell leukemia provides a model of disseminated human B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkins lymphoma (NHL). This model was used to evaluate and compare the anti-leukemic efficacy of recombinant cytokines rIL-1 beta, rIL-2, rIL-6, rTNF alpha, rG-CSF, rGM-CSF and their combinations. Of these 6 cytokines tested, rG-CSF, rIL-1 beta, rIL-2, and rTNF alpha exerted a marked anti-leukemia/lymphoma activity, as reflected by significantly improved survival of treated mice after inoculation of BCL-1 cells. Notably, no additive or synergistic effects were observed when 2-4 cytokines were used in combination. To our knowledge, this report represents the first comparative analysis of recombinant cytokine treatment regimens in an animal model of disseminated B-lineage ALL/NHL.
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PMID:Treatment of BCL-1 murine B-cell leukemia with recombinant cytokines. Comparative analysis of the anti-leukemic potential of interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and their combination. 128 65

The IgE-dependent activation of mononuclear phagocytic cells through their capacity to express low affinity IgE receptors (Fc epsilon RII) has been proposed as a mechanism for the development of airways inflammation in allergic asthma. This Fc epsilon RII expression leads to the IgE-dependent production of the potent pro-inflammatory cytokines IL-1 beta and TNF-alpha. Expression by monocytes of Fc epsilon RII is regulated by several cytokines including interleukin-4, gamma- and alpha-interferons, and granulocyte-macrophage and macrophage colony stimulating factors. An anti-inflammatory effect of nedocromil on monocytes has been proposed as a possible mechanism for its anti-asthma activity. We therefore investigated the capacity of nedocromil to modulate mononuclear phagocyte Fc epsilon RII expression and cytokine production. We used an anti-Fc epsilon RII antibody and flow cytometric analysis to assess the capacity of nedocromil to modulate cytokine-induced Fc epsilon RII expression in normals and asthmatics. Monocytes, THP-1 monocyte leukaemia cells, and alveolar macrophages were exposed to varying concentrations of these cytokines for 48 hr at 37 degrees C with or without the additional presence of nedocromil (1-10 microM) and the per cent of monocytes expressing Fc epsilon RII was determined. No changes in Fc epsilon RII expression were observed. Subsequently, we investigated the capacity of nedocromil to affect the capacity of IgE plus anti-IgE complexes, allergen, and LPS (16 hr/37 degrees C) to stimulate IL-1 beta and IL-6 production. No changes were observed when nedocromil was applied concomitant with the stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anti-inflammatory effects of nedocromil sodium: inhibition of alveolar macrophage function. 133 83

Different normal and malignant human B-cell populations were studied with a twofold aim: to define which cytokines are produced in vivo, and to assess the relationship between cytokine production and kinetic state. To analyse normal B-cells representative of different stages of activation and proliferation in vivo, we purified germinal centre (GC)-B blasts and mantle B (M-B) cells from tonsils. To compare malignant B lymphocytes with their closest normal equivalent cells, we separated malignant CD5+B lymphocytes from the peripheral blood of patients with B-chronic lymphocytic leukemia (B-CLL) and normal CD5+B lymphocytes from cord blood. The expression of interleukins (IL) IL-1 alpha, IL-1 beta, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), IL-2, IL-4, and IL-6 genes was analysed using Northern and Western blotting techniques. TNF-alpha mRNA is produced by resting (M-B) and actively proliferating (GC-B) normal B lymphocytes. TGF-beta mRNA is present at high levels in resting normal M-B cells, while the transcript levels are lower in proliferating GC-B and in activated CD5+B lymphocytes. IL-2 production is limited to the actively proliferating GC-B blasts, IL-1 beta and IL-6 to resting M-B cells. The cytokine production profile of CD5+ malignant B-CLL cells differs from that of their putative normal counterparts and is more like the profile of M-B cells, since B-CLL cells produce IL-1 beta, TNF-alpha, TGF-beta, and IL-6. These observations lead to the following conclusions: among normal B lymphocyte populations, resting M-B lymphocytes are the most active cytokine producers, and B-CLL malignant B cells reflect the production pattern of normal resting B lymphocytes.
Leukemia 1992 Feb
PMID:Molecular investigation of the cytokines produced by normal and malignant B lymphocytes. 137 70

Tumor necrosis factor (TNF) is a macrophage-derived cytokine that causes hemorrhagic necrosis of several human tumors in vitro. It has a wide range of biologic effects including stimulation of secretion of both granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) by normal adult lung fibroblasts in culture. No in vivo data are available on the effect of exogenously administered TNF on cytokine production. In the studies reported here, we show that G-CSF accumulates in the serum in vivo in response to recombinant TNF (rTNF) administration. At the peak of the response circulating levels of 2-6 ng/ml of biologically active G-CSF are detectable. Surprisingly, circulating levels of GM-CSF, interleukin-3 as well as a number of other cytokines were not detectable within the limits of the assays. The results indicate that the levels of GM-CSF or interleukin-3 are minimally 100-fold lower than the peak levels of G-CSF. These data illustrate the complex interplay that cytokines have in vivo. Understanding these interactions in humans is crucial to the correct use of this new class of agents in the clinic.
Leukemia 1992 Apr
PMID:Recombinant human TNF-alpha stimulates the secretion of granulocyte colony-stimulating factor in vivo. 137 4

Oncostatin M (OSM) is a 28-kDa glycoprotein produced by stimulated macrophages and T lymphocytes that inhibits the proliferation of a number of different cell lines derived from solid tumors. Analysis of both amino acid sequence and gene structure has demonstrated that OSM is a member of a cytokine family that includes leukemia inhibitory factor (LIF), IL-6, and granulocyte colony-stimulating factor (G-CSF). We demonstrate that, like LIF, IL-6 and G-CSF, OSM can induce the differentiation of the myeloblastic M1 murine leukemia cells into macrophage-like cells. The morphologic and functional changes induced by OSM are more similar to those observed with LIF and IL-6 than those induced with G-CSF. OSM can also induce the differentiation of the histiocytic U937 human leukemia cells in the presence of granulocyte-macrophage CSF, a property shared with LIF and IL-6. In murine M1 cells, binding of labeled OSM is completely inhibited by excess LIF or OSM, reflecting the binding of OSM to the high affinity form of the murine LIF receptor. In contrast, the binding of labeled OSM to human U937 leukemia cells is inhibited by OSM, but the inhibition by LIF is significantly less. These results suggest that, in human leukemia cells, OSM may act through the LIF receptor and an OSM-specific receptor. The existence of an OSM-specific receptor was confirmed by both growth inhibition and competition binding assays on A375 human melanoma cells. The growth of human A375 cells was inhibited by OSM and IL-6 but not LIF or G-CSF. Neither LIF, G-CSF, nor IL-6 could compete with the binding of labeled OSM to A375 cells.
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PMID:Oncostatin M is a differentiation factor for myeloid leukemia cells. 138 37

The immunosuppressive drugs FK506 and cyclosporin A have an identical spectrum of activities with respect to IgE receptor (Fc epsilon RI)-mediated exocytosis from mast cells and T cell receptor-mediated transcription of IL-2. These findings suggest a common step in receptor-mediated signal transduction leading to exocytosis and transcription and imply that immunosuppressive drugs target specific signal transduction pathways, rather than specific cell types. This hypothesis is supported by studies on the effect of rapamycin on IL-3 dependent proliferation of the rodent mast cell line PT18. Rapamycin inhibits proliferation of PT18 cells, achieving a plateau of 80% inhibition at 1 nM. This inhibition is prevented in a competitive manner by FK506, a structural analogue of rapamycin. Proliferation of rat basophilic leukemia cells and WEHI-3 cells was also inhibited, at doses comparable to those shown previously to inhibit IL-2-dependent proliferation of cytotoxic T lymphocyte line (CTLL) cells. In contrast, proliferation of A-431 cells, a epidermoid cell line, was not affected by rapamycin. DNA histograms indicate that complexes formed between the rapamycin-FK506-binding protein (FKBP) and rapamycin arrest-proliferating PT18 cells in the G0/G1-phase. It is concluded that FKBP-rapamycin complexes may inhibit proliferative signals emanating from IL-3 receptors, resulting in growth arrest of cytokine-dependent, hematopoietic cells.
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PMID:The effect of the immunophilin ligands rapamycin and FK506 on proliferation of mast cells and other hematopoietic cell lines. 138 15

Murine mast cells produce cytokines in response to cross-linking of high affinity receptors for IgE (Fc epsilon RI). Murine mast cells also express the two types of low-affinity receptors for IgG, murine (m)Fc gamma RII, and mFc gamma RIII. We examined the ability of mFc gamma R to trigger a cytokine response such as TNF-alpha production by mast cells. We found that the mFc gamma RII- and mFc gamma RIII-positive mouse mastocytoma cells MMC-1 released TNF-alpha when challenged with F(ab')2 fragments of the rat anti-mFc gamma RII/III 2.4G2 mAb and mouse anti-rat IgG F(ab')2. The release of TNF-alpha was preceded by an increase in TNF-alpha transcripts. mFc gamma RII and mFc gamma RIII have 95% homologous extracellular domains but unrelated transmembrane and intracytoplasmic (IC) domains. mFc gamma RII are single chain receptors whereas mFc gamma RIII associate with a homodimeric gamma-chain that also associates with Fc epsilon RI and TCR. In order to analyze the ability of mFc gamma RII and III to trigger the synthesis of TNF-alpha, we studied RBL-2H3 cells transfected with corresponding cDNA. Rat basophilic leukemia (RBL) transfectants expressing mFc gamma RIII produced TNF-alpha in response to 2.4G2 F(ab')2, but not transfectants expressing mFc gamma RII. Non-transfected RBL cells and mFc gamma RII- or mFc gamma RIII-expressing transfectants, however, released TNF-alpha in response to a rat IgG2a mAb. The respective roles of the alpha and gamma subunits of mFc gamma RIII were examined by studying the production of TNF-alpha by RBL cells expressing deletant and chimeric mFc gamma R. The deletion of intracellular amino acids of the Fc gamma RIII alpha subunit did not prevent 2.4G2 F(ab')2 from triggering the synthesis of TNF-alpha. The substitution of the IC domain of mFc gamma RII for that of mFc gamma RIII gamma, but not that of Fc gamma RIII alpha, enabled 2.4G2 F(ab')2 to trigger the release of TNF-alpha by RBL transfectants. A cytokine response can therefore be induced in mouse and rat mast cells through Fc gamma R. This response is triggered upon cross-linking of mFc gamma RIII but not mFc gamma RII. It depends on the IC sequences of the gamma but not of the alpha subunit of mFc gamma RIII.
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PMID:Induction of tumor necrosis factor-alpha production by mast cells via Fc gamma R. Role of the Fc gamma RIII gamma subunit. 138 72

Immunological parameters were evaluated in patients treated with cytokine-mediated immunotherapy (CMI) consisting of low doses of recombinant human interferon alpha 2a (rIFN alpha) and recombinant human interleukin-2 (rIL-2) administered either concomitantly or sequentially by subcutaneous self-injections in an outpatient setting. Twenty-six patients with hematological malignancies and 2 metastatic melanoma patients in a progressive stage were enrolled in this clinical trial. Of the 26 patients, 24 were at a stage of minimal residual disease, including 14 patients who had received autologous bone marrow transplantation (ABMT) 2-5 months previously, 7 chronic myelogenous leukemia (CML) and 3 acute myeloid leukemia (AML) patients. Two patients (1 CML and 1 mult. myeloma) were treated at a stage of progressive disease. Non-MHC-restricted cytotoxicity directed against natural-killer(NK)-resistant (Daudi) and NK-sensitive (K562) target cells was assessed before, during and after CMI, either in fresh peripheral blood samples (spontaneous activity) or after in vitro rIL-2 activation (induced activity). Spontaneous killing activity was low prior to treatment, but increased upon termination of treatment in 10/15 evaluated cycels. rIL-2-activated cytotoxicity in vitro was markedly elevated in 8/12 and 6/8 patients after one and two cycles, respectively, of sequential treatment, as well as in 3/8 CML and 5/6 patients after one and two cycles, respectively, of concomitant treatment. Activation of the T cell mitogenic response was demonstrated in 6/9 patients after concomitant CMI, while no such effect was observed throughout a sequential treatment in lymphoma and leukemia patients after ABMT. Although a direct correlation between immune stimulation and the in vivo antitumor response cannot yet be determined, our clinical observations support a beneficial therapeutic effect in a substantial number of patients. These results indicated that the ambulatory CMI protocol of rIL-2 and rIFN alpha could stimulate the host defense immune system and may be helpful in mediating the in vivo antitumor response in patients with minimal residual disease.
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PMID:Immunological evaluation of patients with hematological malignancies receiving ambulatory cytokine-mediated immunotherapy with recombinant human interferon-alpha 2a and interleukin-2. 139 43

The hepatic action of cytokines has generally been analysed in terms of the acute-phase response of the liver. The qualitative and quantitative changes in the expression of plasma proteins serve as defining criteria for cytokine function. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) are representatives of a group of cytokines which display strikingly similar effects in both human and rodent liver cells. Hallmarks of the action of these cytokines are the stimulation of type 2 acute-phase plasma proteins and enhancement of the effect of interleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha) on type 1 acute-phase plasma proteins. The transcriptional activation of the various acute-phase plasma protein genes involves common cis-acting regulatory elements whose sequences and location relative to the transcription start site vary from gene to gene. The activity of the IL-6- and LIF-responsive genes depends in part on transcription factors including several members of the C/EBP family, JunB and the glucocorticoid receptor. The expression of these transcription factors is in turn under cytokine-specific control. In a few cases, expression is temporally correlated with the activation of 'late' acute-phase protein genes. The finding that structurally distinct cytokines interact with separate receptors but elicit an almost identical liver cell response demands a reassessment of the contribution of each factor to the in vivo acute-phase response.
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PMID:The action of interleukin 6 and leukaemia inhibitory factor on liver cells. 142 8


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