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 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

We have previously demonstrated that the low number of interleukin-4 receptors (IL-4Rc) on HL-60 leukemia cells render this population susceptible to differentiation by IL-4. As it occurs with normal human monocytes, IL-4 induces the expression of HLA-DR surface antigens on HL-60 cells as well. The second messenger pathway(s) involved after the IL-4 stimulation leading to class II up-regulation has not been fully examined. Here we show that IL-4-induced class II antigen expression on the HL-60 cell line or normal human monocytes is calcium/calmodulin-independent since theophylline (TPH, a calmodulin inhibitor) does not block the IL-4 effect. In addition, the pyruvate kinase C (PKC) pathway does not seem to participate in the process either because in our system activation of PKC by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) is insufficient by itself to induce HLA-DR. We found, however, that a second messenger pathway can be mediated by a G protein system since IL-4 concomitantly induces class II and p21ras expression which can be successfully blocked by a highly specific anti-p21ras monoclonal antibody. In addition, using another p21ras inducer, the 5-azacytidine C (5-AzaC), we showed that this agent can also induce the expression of p21ras and class II, both of which can be inhibited by the same antibody. Thus, it appears that IL-4 selects the G protein system as a signaling pathway in order to exert its action for the induction of HLA-DR on human normal monocytes or M2 leukemia target cells. Since monocytes and macrophages participate in virtually all immune reactions, the regulation of class II induction is of obvious importance.
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PMID:The p21ras protein as an intermediate signaling molecule in the IL-4-induced HLA-DR expression on normal and leukemic human myeloid cells. 137 87

Since autocrine stimulation by tumor necrosis factor-alpha (TNF alpha) may be implicated in the proliferation of normal and malignant B cells, we measured the production of TNF alpha protein by these cells in response to various B-cell stimulatory agents. Purified malignant and non-malignant B lymphocytes were incubated with interleukin-4 (IL4), interferon-alpha (IFN alpha) and IFN gamma, and the supernatants were tested for the production of TNF alpha using an enzyme-linked immunosorbent assay (ELISA). Chronic lymphocytic (CLL) and prolymphocytic (PLL) leukemia cells produced low amounts of TNF alpha, irrespectively of the addition of inducers. Normal B lymphocytes (tonsillar and blood) produced TNF alpha, but the level was not influenced by any of the inducers tested. Hairy cell leukemia (HCL) cells produced TNF alpha in the absence of stimuli and this production was markedly enhanced by addition of IFN alpha or, to a lesser extent, by IFN gamma and IL4. These results contradict the hypothesis that IFN alpha exerts its therapeutic action in HCL by inhibition of autocrine TNF alpha production.
Leukemia 1992 Feb
PMID:Production of tumor necrosis factor-alpha by normal and malignant B lymphocytes in response to interferon-alpha, interferon-gamma and interleukin-4. 842 86

Using two complementary culture systems, suspension and clonal cultures, and with a method of graphic display (star diagram), we studied the effects of recombinant human interleukin-4 (IL-4) on leukemic stem cell renewal and differentiation in acute myelogenous leukemia (AML). The interactions between IL-4 and other recombinant human cytokines, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), macrophage CSF (M-CSF) and interleukins-1 alpha, -2, -3, -5, and -6 were also studied. IL-4 alone had significant effects on both self-renewal and differentiation of blast progenitors in some cases; in clonogenic assay, IL-4 stimulated blast colony formation and in one case IL-4 was the most powerful stimulator among the nine growth factors tested. Star diagrams, constructed using the data from both suspension and clonal cultures, showed that IL-4 could influence the balance between self-renewal and differentiation of clonogenic cells. Negative and positive interactions were detected between IL-4 and other cytokines in suspension culture. These results indicate that IL-4 is a cytokine with a potential role in regulating the growth of myeloid leukemic stem cells, and that IL-4 may be useful in treating selected AML patients.
Leukemia 1991 Feb
PMID:Interleukin-4 as a growth regulator of clonogenic cells in acute myelogenous leukemia in suspension culture. 170 33

We previously documented that a single BCL1 leukemia cell can produce mu and gamma 1 immunoglobulin heavy chains with identical variable segments in an allelically excluded fashion without heavy chain constant region gene rearrangement. To understand the mechanism of dual mu/gamma 1 synthesis in BCL1 subclones, we have analyzed mature and pre-RNA at the nascent and steady-state levels. We find mu and gamma 1 sequences linked in pre-RNA. However, the primary mu and gamma 1 transcription units are about the same length (approximately 15 kilobases). Initiation of gamma 1 pre-RNA occurs upstream of C gamma 1 at sites identical to those seen in lipopolysaccharide/interleukin-4-induced normal B cells. We propose that dual mu/gamma 1 RNA synthesis occurs by a discontinuous transcription mechanism involving either trans-splicing or ligation of mu pre-RNA initiated 5' of the variable-diversity-joining region to gamma 1 pre-RNA initiated 5' of C gamma 1.
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PMID:Coexpression of mu and gamma 1 heavy chains can occur by a discontinuous transcription mechanism from the same unrearranged chromosome. 174 77

We investigated the effect of recombinant human interleukin-4 (rhIL-4) on the in vitro growth of human leukemia cells in liquid culture and 3H-thymidine incorporation and found inhibitory effects on the growth of leukemic cells from patients with Ph1-positive acute lymphoblastic leukemia (Ph1 ALL) and three Ph1 ALL cell lines. However, no inhibitory effects were seen in Ph1-positive leukemic cell lines derived from patients with chronic myelogenous leukemia in blast crisis and various types of Ph1-negative leukemia cells, including B-lineage leukemia cells. In a flow cytometry assay of IL-4 receptor (IL-4R), all three Ph1-positive ALL cell lines showed the presence of IL-4R on their cell surfaces, and the IL-4-dependent inhibition on the growth of Ph1-positive ALL cells was abrogated by the addition of either monoclonal or polyclonal antibodies against rhIL-4. Other cytokines, including IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and IL-6, showed no inhibitory effects on the growth of Ph1-ALL cells, but tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-alpha, -beta, and -gamma displayed slight inhibitory effects in a high concentration. The growth inhibition induced by rhIL-4 in the Ph1-positive ALL cells was not abrogated by the addition of antibodies against either IFN-gamma or TNF-alpha. Furthermore, these cells showed no significant production of IFN-alpha, -beta, or -gamma or TNF-alpha after exposure to rhIL-4, thus indicating that the growth inhibition of Ph1-positive ALL cells by rhIL-4 is not associated with IL-4-stimulating production of these factors. rhIL-4 caused significant inhibition of the tyrosine kinase activity in these Ph1-positive ALL cells, similar to Herbimycin A, an inhibitor of tyrosine kinase that inhibited the tyrosine kinase activity in these cells. Our finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibilities for patients with Ph1-positive ALL.
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PMID:Inhibitory effect of interleukin-4 on the in vitro growth of Ph1-positive acute lymphoblastic leukemia cells. 188 23

Treatment of splenic B lymphocytes and certain B-lineage cell lines with the mitogen lipopolysaccharide (LPS) and the lymphokine interleukin-4 (IL-4) induces expression of germ line immunoglobulin C epsilon transcripts and class switching to the C epsilon gene. We show that LPS-plus-IL-4 induction of germ line epsilon transcripts (termed I epsilon transcripts) occurs at the transcriptional level in an Abelson murine leukemia virus-transformed pre-B-cell line. A 1.1-kb region of DNA surrounding the I epsilon promoter endows inducible transcription to a heterologous reporter gene stably transfected into these cells; such inducible expression depends on combined treatment with LPS and IL-4. Analyses of constructs transiently introduced into a B-cell lymphoma line demonstrated that LPS-plus-IL-4-inducible expression can be conferred by a 179-bp segment of DNA spanning the I epsilon transcriptional initiation site. Mutational analyses demonstrated that this expression depended on DNA sequences within a conserved region directly upstream from the I epsilon transcriptional initiation region. One nuclear protein that is constitutively expressed in normal B cells binds to the downstream end of the conserved sequence; its binding specificity correlates with the functional effect of several mutations. Two additional proteins, which are induced by IL-4 treatment of splenic B cells, bind to the transcription initiation sites of I epsilon. These proteins are indistinguishable in binding assays from proteins previously shown to bind an enhancer region of the class II major histocompatibility complex gene A alpha.
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PMID:Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. 192 63

Evidence is presented that human monocytes and acute myeloblastic leukemic (AML) cells contain both high and low affinity binding sites for interleukin-4 (IL-4). On monocytes 183 +/- 132 high affinity binding sites per cell with a Kd of 60 +/- 29 pM and 1500 +/- 600 low affinity receptors with a Kd of 2.3 +/- 0.4 nM (X +/- S.D., n = 6) could be demonstrated. On AML cells (n = 11) a comparable number and binding affinity of IL-4 receptors were observed (77 +/- 36 high affinity receptors with Kd 72 +/- 31 pM and 2400 +/- 1000 low affinity receptors with Kd of 2.2 +/- 0.7 nM). In addition, no cross-competition was shown between radiolabeled IL-4 and IL-1-alpha, IL-3, IL-6, IL-7, G-CSF, and GM-CSF. Both types of receptors on monocytes as well as on leukemic blasts could be down-modulated in a similar fashion by IL-4 and activators of protein kinase C (PKC), but not by the calcium ionophore A23187. The down-modulation by PKC activators was caused by an increased internalization, degradation and release of radiolabeled IL-4 in the medium. Finally, the functionality of the IL-4 receptors were tested on AML cells with a 3H-thymidine proliferation assay. In 8/11 cases IL-4 affected AML proliferation. These data demonstrate two different binding sites for IL-4 on normal and leukemic cells, which can be modulated by external activation signals in an analogous way.
Leukemia 1991 Sep
PMID:Expression and regulation of IL-4 receptors on human monocytes and acute myeloblastic leukemic cells. 194 30

T-cell-replacing factor (TRF) is a T-cell-derived factor required for terminal differentiation of activated B cells to immunoglobulin-secreting cells. Previous studies have shown that a murine T-cell hybrid (B151K12) produces factor(s) that (i) induce immunoglobulin secretion by the B-cell leukemia line BCL1 and secondary anti-2,4-dinitrophenyl IgG synthesis in vitro by dinitrophenyl-primed B cells (TRF activity) and (ii) cause proliferation of the BCL1 cells [B-cell growth factor II (BCGF-II) activity]. Both activities appear to be associated with the same molecule. Here we report the production of a monoclonal antibody to murine TRF. The monoclonal antibody, designated TB13, strongly inhibited both TRF and BCGF-II activities and absorbed TRF- as well as BCGF-II-active molecules produced by B151K12 and by Xenopus oocytes that had been injected with mRNA transcribed from plasmid pSP6K-mTRF23. Inhibition was linearly dependent on the concentration of both TB13 and TRF. Monoclonal antibody TB13 did not inhibit the activities of B-cell stimulatory factor 1, interleukin 1, interleukin 2, or interleukin 3. TRF activity in dissolved samples of immunoprecipitates obtained with TB13 was recovered after NaDodSO4/PAGE, in the fractions corresponding to a protein band at Mr 46,000. Our results indicate that monoclonal antibody TB13 recognizes a molecule that has both TRF and BCGF-II activities.
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PMID:Production of a monoclonal antibody useful in the molecular characterization of murine T-cell-replacing factor/B-cell growth factor II. 244 25

Induction of differentiation in B lymphoma/leukemia cells with interleukins was compared with differentiation induced by phorbol ester (TPA) and pokeweed mitogen (PWM) or by 8-bromo-guanosine. Both cell surface changes and monoclonal immunoglobulin (Ig) secretion were followed as markers of differentiation. The results indicate great similarity in the differentiation patterns induced by interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-4 (IL-4), with regard to Ig secretion and changes in surface markers. Induction of Ig secretion and surface marker changes by 8-bromo-guanosine was similar to that induced by TPA and PWM; however, for some markers, cell surface changes induced by TPA and PWM or by 8-bromo-guanosine were quite different from those induced by the three interleukins tested. Whereas all three interleukins stimulated the expression of CD5, PWM and TPA and 8-bromo-guanosine substantially decreased CD5 expression on B lymphoma cells. Differences were also observed in the effect on the expression of surface Ig and on the expression of CD19 and CD20. Interestingly, the three interleukins tested and 8-bromo-guanosine induced differentiation and Ig secretion within 24 to 48 hours with no prior activation by B-cell activators, such as anti-surface Ig antibody. These results suggest that leukemic B cells are arrested at a point distal to activation and first cell division. Moreover, the similarity in Ig secretion and surface changes induced by TPA and PWM or 8-bromo-guanosine suggest a similar pathway; however, this pathway is different from the differentiation signal induced by the three interleukins.
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PMID:Induction of surface marker changes and monoclonal idiotypic immunoglobulin secretion in lymphoma/leukemia cells: comparative study with interleukin-1, interleukin-2, interleukin-4, 8-bromo-guanosine, pokeweed mitogen, and tetradecanoyl phorbol-13-acetate. 261 Sep 49


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