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)

The basophilic leukaemia cell line KU812 can be induced to differentiate into basophil-like cells in vitro when exposed to supernatant from the Mo T-cell line. KU812 cells express affinity receptors for IgE, produce histamine and tryptase and have the capacity for IgE-mediated histamine release. In this study we have examined the cytokines, produced by the Mo cell line, which are responsible for the observed differentiation-inducing effect in the KU812 cell line. It was shown that interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) induced differentiation in the KU812 cells and that these cytokines were responsible for the differentiation-inducing effect of the Mo supernatant. Other cytokines tested, IL-1 beta, IL-2, IL-4, IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and nerve growth factor (NGF) were without effect on the KU812 cells. KU812 was also shown to express receptors for both TNF-alpha and IL-6 after 3 days cultivation with conditioned media from the Mo T-cell line. Untreated cells showed no detectable levels of TNF-alpha or IL-6 receptors indicating induction of these receptors during differentiation. Spontaneous differentiation was shown to occur under serum-free conditions which may be the result of endogenous IL-6 production through an autocrine loop. The activity of TNF-alpha and IL-6 could be blocked by specific monoclonal antibodies (mAb) to the respective cytokine.
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PMID:TNF-alpha and IL-6 induce differentiation in the human basophilic leukaemia cell line KU812. 813 23

The present study investigates the effect of transforming growth factor (TGF)-beta on the production of IL-4 and IFN-gamma by the leukemia Th0 type cell line HUT78, by freshly isolated human T cells, and by antigen specific human T cell clones. We found that IL-4 and IFN-gamma, but not IL-2, production by stimulated HUT78 cells was inhibited by TGF-beta 1. TGF-beta 1 also reduced the accumulation of IL-4 and IFN-gamma specific mRNA in stimulated HUT78 cells. However, IL-2 and IL-7 co-stimulated IL-4 and IFN-gamma production, whereas IL-1, IL-3, IL-5, IL-6, IL-8, tumor necrosis factor-alpha or granulocyte macrophage colony stimulating factor had no effect. Because IL-2 is an important helper cytokine for the production of IL-4 and IFN-gamma, we investigated whether signal transduction through the IL-2 receptor is impaired by TGF-beta 1. We found that tyrosine phosphorylation in response to IL-2 in HUT78 cells was strongly inhibited by a short preincubation with TGF-beta 1. Evidence for an antagonistic role for TGF-beta 1 and IL-2 comes from the finding that high doses of IL-2 could partially overcome TGF-beta 1 mediated inhibition of IL-4 and IFN-gamma production. Similar to its effect on HUT78 cells, TGF-beta 1 also inhibited IL-4 and IFN-gamma production by freshly isolated T cells as well as by human T cell clones. Taken together, our experiments show that the IL-2 dependent cytokines IL-4 and IFN-gamma are both negatively controlled by TGF-beta under conditions where IL-2 production is unaffected by a mechanism which partially involves an inhibition of IL-2/IL-2R signal transduction. These data identify TGF-beta and IL-2 as mutual antagonists in the regulation of IL-4 and IFN-gamma production.
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PMID:Transforming growth factor-beta inhibits IL-4 and IFN-gamma production by stimulated human T cells. 818 98

Cytokine treatment in patients with myelodysplastic syndrome (MDS) aims to overcome the maturation defects of myeloid lineage cells associated with cytopenia and cellular dysfunction of mature cells. Since phagocytes play a major role in host defense against microbial infection, we investigated cytokine secretion and oxygen radical release (ORR) from peripheral blood monocytes (PBMC) in a total of 16 MDS patients, 12 patients with refractory anemia (RA) and four patients with RA and excess of blasts (RAEB). Interleukin (IL-6), tumour necrosis factor alpha (TNF alpha), IL-1 beta, and IL-8 secretion from monocytes in response to lipopolysaccharide (LPS) was significantly reduced in the 12 patients with RA compared to 12 healthy controls, whereas no difference was seen in ORR. We further assessed cytokine secretion from monocytes of 10 MDS patients before and after therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, or a combination therapy with GM-CSF and cytosine arabinoside (AraC). In all 10 patients, secretion of IL-1 beta, IL-6, and TNF alpha from PBMC increased after cytokine therapy, whereas IL-8 secretion increased only in five patients with GM-CSF or IL-3 therapy receiving a dosage > or = 250 micrograms/m2 per day but decreased in all other patients. ORR increased in all patients on either GM-CSF or IL-3 therapy. These data indicate that the ability of monocytes to secrete secondary cytokines is impaired in MDS patients but can be restored by in vivo administration of GM-CSF and IL-3.
Leukemia 1993 Nov
PMID:Restoration of impaired cytokine secretion from monocytes of patients with myelodysplastic syndromes after in vivo treatment with GM-CSF or IL-3. 823 Dec 42

To define the structural features important for IL-8 binding to its two known receptors, mutants of IL-8 and melanoma growth-stimulating activity (MGSA) and chimerae consisting of segments of these two chemokines were constructed and purified from the pGEX 2T Escherichia coli expression vector. IL-8 alpha and beta receptors were expressed stably and individually in 293 kidney epithelial cells and HL60 human leukemia cells. The Kd for IL-8 itself and copy numbers for both receptors in transfected cells were comparable. Competition binding with 125I-labeled IL-8, however, showed large differences for several of the IL-8 mutants between alpha and beta receptors. The amino-terminal ELR sequence was important for IL-8 binding to the alpha receptor, but not sufficient for high affinity binding. Both rabbit IL-8 and MGSA share the ELR sequence with human IL-8, but compete poorly with it. The carboxyl terminus distal to amino acid 50 does not seem to mediate high affinity binding to the alpha receptor. A rabbit IL-8/human IL-8 chimera that differs in only eight amino acids from the human IL-8 sequence, was 150-fold lower in its affinity for the alpha receptor than human IL-8. In contrast, both the amino and carboxyl termini appear to be important for binding to the beta receptor. If the ELR sequence of IL-8 was substituted with alanines or if the carboxyl terminus distal to C50 was replaced with the MGSA sequence, a reduction occurred in binding competition. If both changes were introduced simultaneously, binding was abolished. Binding of MGSA was completely prevented by replacement of the ELR sequence with alanines. Ca2+ mobilization in HL60 cells transfected with the alpha or beta receptor was used to assess cell stimulation. The various mutant forms of IL-8 induced receptor activity with a pattern of sensitivity parallel to the competition binding affinities, indicating that both receptors are active.
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PMID:Multiple sites on IL-8 responsible for binding to alpha and beta IL-8 receptors. 824 75

The cell line AG-F was isolated from the marrow of a neuroblastoma patient undergoing myeloablative treatment and autologous bone marrow rescue. A year later, the patient developed a Hodgkin's type lymphoma. AG-F cell line demonstrated an unusual phenotype, lacking surface CD2 and CD3, but expressing high levels of CD4, CD5, CD7, CD29, and CD45RO. Markers associated with Hodgkin's lymphoma cells, CD15 and CD30, were also positive. AG-F cells grow in suspension in clusters of 50-200 cells, with a doubling time of 9 h. They can also grow in serum-free medium and form tumors in nude mice. AG-F cells have amplified N-myc and c-myc and high levels of the corresponding mRNA transcripts. Cytogenetic analysis revealed a DNA index by flow cytometry of near tetraploid cells and a karyotype of 85-87 chromosomes, with consistent abnormalities in chromosomes 1, 5, and 9. Gene rearrangement studies revealed rearrangement of the beta gene of the T-cell receptor. AG-F cells secrete high levels of IL-6, IL-8, IL-10, and GM-CSF. Cell adherence and formation of long processes could be induced by fibronectin and were enhanced by exposure to PMA. Cells exposed to phorbol myristate acetate (PMA) had increased expression of CD11a, CD11b, CD18, CD45RO, and HLA-DR, whereas expression of CD15 and CD30 was markedly decreased. Similarly, the level of c-myc and N-myc oncoproteins and the levels of the cytoskeletal proteins, actin, tubulin, and vimentin markedly decreased early after PMA-induced differentiation.
Leukemia 1993 Dec
PMID:Isolation and characterization of an early T-helper/inducer cell line with a unique pattern of surface phenotype, constitutive cytokine secretion and myc oncogene expression. 825 4

Numerous cytokines are present in inflammatory foci. Two of them, interleukin-1 (IL-1) and tumour necrosis factor (TNF), play a major role in coordinating mechanisms which command inflammation. Under their action many cells produce lipidic mediators, proteolytic enzymes or free radicals, all factors that are directly responsible for the noxious effects observed. IL-1 and/or TNF exert cytotoxic activities on vascular epithelium, cartilage, bone, muscle or beta cells of pancreatic islets. Such cytokines as interferon gamma (IFN gamma), IL-3 or granulocyte-macrophage colony stimulating factor (GM-CSF) amplify the inflammatory response by increasing the production of IL-1 and TNF by macrophages. GM-CSF also produces other cytokines, such as IL-8 and the macrophage chemoattractant protein 1 (MCP-1), the chemotactic properties of which participate in the recruitment of leucocytes within the focus of inflammation. IL-6 abounds in inflammatory processes and induces the production by hepatocytes of acute inflammation phase proteins. The same applies to IL-1, TNF, IL-11, the leukaemia inhibitory factor (LIF) or the transforming growth factor beta (TGF beta). The latter also possesses a number of anti-inflammatory activities and, like IL-4 and IL-10, can inhibit IL-1 and TNF production. Glucocorticoids have this potential activity, and they may be produced by a cascade of events initiated by IL-1, TNF and IL-6, involving the neuroendocrine system. The concept of "cytokine network", therefore, perfectly illustrates the participation of these mediators in inflammatory mechanisms.
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PMID:[Cytokines and inflammation]. 834 24

We looked for chemotaxin/interleukin 8 (CT/IL-8) activity in the culture fluids of 97 human leukemia cell lines and found it in two of the T cell lines, six of the myeloid cell lines, and one of the normal B-cell lines. It was particularly strong in the culture fluids of two cell lines. These cell lines secreted a chemotactic protein into the culture fluids under certain conditions of stimulation with phorbol-12-myristate 13-acetate (PMA), lipopolysaccharide, or hemagglutinin-P. A myeloid leukemia cell line, ML-1, secreted an inducible chemotaxin when stimulated with PMA (1 ng/ml) for 24 h. We purified the chemotaxin from ML-1 cell culture fluid using an improved procedure: concentration with DEAE-Sepharose CL-6B and CM-Sepharose CL-6B, CM-Sepharose column chromatography, and reverse-phase 5TMS-300 column on HPLC with the retention time coinciding with that of LUCT/IL-8 [Suzuki et al., 1989, J. Exp. Med. 169, 1895]. The yield was 200 micrograms protein from 6 liters of the culture fluid. The N terminus of CT/IL-8 was AVLPR-SAKELRXQXIKTYSK- - -, the same as that of LUCT/IL-8, which is constitutively secreted from lung giant cell carcinoma LU65C cells. The optimal concentration in the chemotactic activity of CT/IL-8, equivalent to that of bacterial chemotactic peptide fMet-Leu-Phe (10 nM), was found to be 5 nM. The results show that this chemotaxin is identical to LUCT/IL-8.
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PMID:Isolation and amino acid sequence of a chemotactic protein, LECT/interleukin 8, from a human myeloid leukemia cell line, ML-1. 834 17

The production of interleukin-2 (IL-2) by phytohemagglutinin (PHA)-stimulated human leukemia T cell lines was significantly increased by 6 different cytokines. The most effective cytokines were interleukin-1 alpha (IL-1 alpha) and IL-1 beta; less effective were interferon-alpha (IFN-alpha), tumor necrosis factor-alpha (TNF-alpha), IFN-beta and TNF-beta. The combinations of two cytokines had synergistic or additive effects and increased IL-2 production to a greater extent than either cytokine alone. Other cytokines tested, such as IL-3, IL-4, IL-6, IL-7, IL-8 and IFN-gamma, had no effect on IL-2 production. However, a remarkable heterogeneity in sensitivity to the enhancing effects of the active cytokines was found among the IL-2-producing T cell lines studied. While IL-2 production in the most sensitive cell line, MOLT-16, was increased by all 6 active cytokines, other cell lines responded by increasing IL-2 production to stimulation with only some of the cytokines tested. The production of IL-2 in T cell line H9 was not enhanced by any of the cytokines used. These results show that several cytokines can increase IL-2 production by having a direct effect on the activated IL-2-producing T cells, but also that the outcome of the regulatory effects of individual cytokines depends considerably upon the individual IL-2-producing T cell clone.
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PMID:Enhancement of interleukin-2 (IL-2) production by 6 different cytokines: heterogeneity among IL-2 producing T cell clones. 834 81

Purified leukemic cells from 30 acute myeloid leukemia (AML) cases at diagnosis were investigated for the presence of interleukin 8 (IL-8) mRNA by Northern blot analysis. IL-8 specific transcripts were detected in uncultured blasts in 14/30 cases, 10/14 from patients with M4-M5 and 4/14 from cases with M0-M3 morphology. The transcript expression was associated with the detection of IL-8 molecule in blast cells by immunostaining performed on cytospin preparations. After 24-hour culture, a strong up-regulation or the appearance in cases negative before culture of IL-8 mRNA was observed in all cases tested, and culture supernatants contained high amounts of IL-8. Our data demonstrate that leukemic cells in AML are equipped with the functional apparatus for IL-8 production. Since IL-8 displays a wide range of biological activities, including the regulation of some membrane molecules relevant to adhesion and migration processes, its production by AML blasts might be of relevance for the pattern of leukemic growth.
Leukemia 1993 Oct
PMID:IL-8 mRNA expression and IL-8 production by acute myeloid leukemia cells. 841 17

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3-dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL-3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM-CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.
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PMID:Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist. 854 80


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