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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crosslinking HLA-DR molecules by monoclonal antibodies (moAbs) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic calcium concentrations in activated human T cells. Binding of bacterial superantigens or moAbs to DR molecules on activated T cells was recently reported to induce homotypic aggregation through activation of protein kinase C (PKC) and mediated by CD11a/CD54 (LFA-1/CAM-1) adhesion molecules. Here, we report that moAbs directed against framework DR, but neither DR1, 2- and DRw52- nor DQ- and DP-specific moABs induced homotypic aggregation of antigen- and alloantigen-activated T cells, antigen-specific CD4+ T-cell lines, a CD8+ T-cytotoxic cell line, and T-leukemia cells (HUT78). Protein tyrosine kinase (PTK) inhibitor herbimycin A partly blocked class-II-induced aggregation responses. In contrast, phorbol ester (PMA)-induced aggregation was essentially unaffected. A potent inhibitor of PKC, staurosporin, inhibited both moAb- and PMA-induced aggregation responses. The aggregation responses were completely inhibited by low temperatures, cytochalasins B and E, and partly inhibited by EDTA and CD18 moAbs, but unaffected by aphidicolin, mitomycin C, an adenylate cyclase inhibitor (2'5'-dideoxyadenosine), and moAbs against other adhesion molecules (CD2/CD58 [LFA-3], CD28/CD28 ligand B7, CD4, and CD44). In conclusion, HLA class-II-induced aggregation responses in activated T cells appear to involve PTK and PKC activation and to be mediated through CD11a-dependent and independent adhesion pathways.
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PMID:Signal transduction by HLA class II molecules in human T cells: induction of LFA-1-dependent and independent adhesion. 128 78

We have earlier found that in Jurkat cells activation of protein kinase C (PKC) enhances the cyclic adenosine monophosphate (cAMP) accumulation induced by adenosine receptor stimulation or activation of Gs. Here we have therefore examined the effect of the phorbol ester PMA (phorbol 12-myristate 13-acetate) which stimulates PKC and a combination of the adenosine receptor agonist NECA (5'-(N-ethyl)-carboxamido adenosine) and forskolin to raise cAMP, on the levels of c-Fos and Jun and on the binding and transcriptional activity of the transcription factor, activator protein-1 (AP-1). PMA treatment caused a concentration- and time-dependent increase in both c-Fos and Jun immunoreactivity in contrast to cAMP elevation that had only a slight effect. Both PMA and the combination of NECA and forskolin acted together either to increase (c-Fos) or decrease (Jun) protein levels as well as increasing AP-1 binding, as judged by gel-shift assay, and AP-1 transcriptional activity. Furthermore there was a clear-cut synergy between the PKC stimulator and the cAMP elevating agents. The results demonstrate that the simultaneous activation of PKC and elevation of cAMP leads to an enhanced AP-1 transcriptional activity in a T-leukemia cell line, suggesting that the previously observed interaction between the parallel signal transduction pathways may have functional consequences at the level of gene transcription.
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PMID:Activation of protein kinase C and elevation of cAMP interact synergistically to raise c-Fos and AP-1 activity in Jurkat cells. 133 18

The defective virus found in the LP-BM5 mixture of murine leukemia viruses induces a severe immune deficiency disease in C57BL/6 mice that is characterized by the activation and expansion of T and B cells that become unresponsive to normal immune stimuli. The nature of the biochemical lesion in these defective lymphocyte populations remains unknown. Flow cytometric analysis of the T cell population in infected animals has demonstrated expansion of both CD4+ and CD8+ subsets. Despite chronic expansion in vivo, CD4+ T cells by wk 4 postinfection failed to up-regulate cell surface IL-2R expression, produced IL-2, or proliferate in vitro in response to either Con A, Staphylococcal enterotoxin super-antigens, or anti-CD3 stimulation. Exogenous IL-2 did not restore the proliferative response and also failed to up-regulate IL-R expression on CD4+ T cells from infected mice, even though basal IL-2R expression was initially elevated compared to normals. In contrast, CD4+ T cells from infected mice could be induced to proliferate by stimulation with PMA and ionomycin resulting in IL-2R up-regulation, IL-2 production, and proliferation. Moreover, proliferation could also be induced by anti-CD3 plus PMA, although anti-CD3 plus ionomycin was without effect. These studies suggest that chronic expansion of CD4+ T cells in infected mice is probably not maintained by normal TCR signaling, which appears defective in these cells. In addition, the lesion in biochemical signaling appears to result in defective activation of protein kinase C, which can be overcome by direct activation with PMA.
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PMID:T-deficient transmembrane signaling in CD4+ T cells of retroviral-induced immune-deficient mice. 135 Feb 88

Human IL-9 is a T cell-derived lymphokine that is abundantly expressed upon activation with mitogens. The observation that IL-9 induction peaks as late as 28 h after stimulation suggested the involvement of secondary signals in this process. The finding reported here that IL-9 expression is blocked by cycloheximide strongly supports this hypothesis. Moreover, we identify IL-2 as the critical element controlling IL-9 expression in T cells. We show (i) that anti-IL-2R antibodies block IL-9 expression in T cells stimulated with PMA and anti-CD3 and (ii) that IL-2, of a panel of cytokines, is the only molecule that synergizes with PMA for IL-9 induction. The latter finding is confirmed in a T cell leukemia line. Finally, we demonstrate that IL-2 plays a regulatory role in the induction of other cytokines, such as IL-4, IL-5, IL-6, and granulocyte/macrophage-CSF, in fresh peripheral T cells.
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PMID:IL-2 dependence of IL-9 expression in human T lymphocytes. 153 52

By using a fluorescence sandwich ELISA for the quantification of soluble human IL-6R, normal human PBMC were found to be induced to release IL-6R into culture supernatant by stimulation with PHA. Furthermore, certain promonocyte cell lines and human T-cell leukemia virus I (HTLV-I)-positive cell lines produced sIL-6R into culture supernatants constitutively. However, this was not found with HTLV-I negative T cell lines and Burkitt's B cell line. In addition, generation of supernatant IL-6R of the promonocyte cell line was significantly increased 27-fold after PMA treatment and sevenfold after infection with HIV. The released IL-6R molecules were characterized as an apparent m.w. of 50 to 55 kDa by both size-exclusion HPLC and immunoprecipitation of the soluble protein with IL-6R-specific mAb followed by SDS-PAGE analysis. Furthermore, increased levels of serum IL-6R were detected in blood donors seropositive for HIV. Moreover, the released IL-6R could bind efficiently to purified rIL-6 on solid phase and suppressed the proliferative responses of PBMC. These results suggest that the release of soluble IL-6R might be linked to regulatory functions of immune responses induced by IL-6 stimulation during normal and human retrovirus-infected cell growth and differentiation.
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PMID:Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. 154 25

CD40 was originally identified on circulating and tonsillar human B cells, and anti-CD40 monoclonal antibodies (MoAb) are known to deliver a progression signal to activated B cells. However, the expression and function of CD40 on human B cell precursors (BCP) have not been examined in detail. Two new anti-CD40 MoAb were produced and shown to recognize an epitope indistinguishable from the anti-CD40 antibody G28-5. CD40 was readily detected on normal and leukemic BCP by flow cytometry, and cell surface expression was upregulated by phorbol ester. Despite the ability of normal and leukemic BCP to respond to phorbol ester (PMA) and/or low molecular weight B cell growth factor (L-BCGF), anti-CD40 exerted no stimulatory action and could not enhance the response of these cells to PMA, L-BCGF, or both. Cross-linking anti-CD40 MoAb with rabbit anti-mouse Ig also failed to induce a proliferative response in normal BCP. We conclude that anti-CD40 does not exert demonstrable agonistic effects on normal and leukemic human BCP. Our results suggest that signal delivery through CD40 and/or subsequent intracellular signal processing may require accessory molecules not expressed in BCP, or CD40 may subserve a different function for BCP.
Leukemia 1990 Nov
PMID:Analysis of expression and function of CD40 on normal and leukemic human B cell precursors. 170 Feb 37

To elucidate the differentiation-associated expression of enzymes catalyzing arachidonic acid metabolism, we measured arachidonate metabolites by reverse-phase high pressure liquid chromatography in monocytoid leukemia (ML-1, THP-1, and U937) and myeloid leukemia (KG-1) cell lines. Undifferentiated ML-1 or THP-1 cells produced trace amounts of eicosanoids via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Upon differentiation induced by phorbol ester (phorbol 12-myristate 13-acetate [PMA]), metabolites via the COX pathway were increased by 100-fold in ML-1 and THP-1 cells, while the LOX products remained barely detectable. All the COX metabolites were elevated, but thromboxane A2 (TXA2) formation was threefold higher in ML-1 cells than in THP-1 cells. Similar time-related increases in COX metabolites were observed in THP-1 cells induced to differentiate with retinoic acid. Undifferentiated U937 cells were capable of generating a much higher quantity of COX products than ML-1 or THP-1 cells, but, upon PMA-induced differentiation, COX products were increased by only two-fold to threefold over the undifferentiated cells and the total COX products in differentiated U937 cells were only one-seventh of those produced by differentiated ML-1 or THP-1 cells. KG-1 cells had an entirely different metabolic profile. They produced a large quantity of a metabolite coeluted with prostaglandin D2, and PMA had no effect on inducing changes in arachidonic acid (AA) metabolism. Increased COX metabolite formation in differentiated THP-1 and ML-1 cells was due to an enhanced level of prostaglandin H synthase enzyme mass, as measured by Western blot analysis. The TXA synthase activity was also increased by approximately 100-fold in PMA-induced ML-1 cells and 10-fold in THP-1 cells. These findings indicate that increased expression of prostaglandin H and TXA synthase enzymes is a feature of differentiated monocytoid leukemia cell lines.
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PMID:Differentiation-associated expression of prostaglandin H and thromboxane A synthases in monocytoid leukemia cell lines. 174 85

PMA treatment of human leukemic cells resulted in a significant increase in the phosphorylation of a 72-kDa protein, which was abrogated by treating the nuclear extracts with DNase I, but additionally stimulated by adding DNA. To be active, DNA must be double-stranded with an average size of 300 base pairs, but shows no apparent species- or sequence-specificity. NP-72 isolated from control or PMA-treated nuclei with 1 mM ATP lacked phosphorylating activity, suggesting it to be a substrate for a dsDNA-stimulated protein kinase(s). Simultaneous exposure of HL-60 cells to PMA and the protein kinase C inhibitor staurosporine diminished the phosphorylation of NP-72. These data suggest that leukemia cell differentiation is accompanied by the induction and/or activation of a dsDNA-stimulated protein kinase whose protein substrates include NP-72 and whose activity is directly or indirectly influenced by protein kinase C.
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PMID:dsDNA-stimulated phosphorylation of a 72-kDa nucleoprotein accompanies PMA-induced HL-60 leukemic cell differentiation. 177 55

Multivalent antigen that is capable of binding to and crosslinking the IgE receptors on rat basophilic leukemia (RBL) cells, induces a rapid and sustained rise in the content of filamentous actin. This reorganization of the actin may be responsible for changes in cellular morphology during the degranulation process. The antigen-stimulated polymerization of actin can be blocked in a dose-dependent manner by protein kinase inhibitors which also block degranulation. Conversely, reagents such as PMA, 1,2-dioctanoyl-sn-glycerol (diC8), and 1-oleoyl-2-acetyl-glycerol (OAG) which stimulate protein kinase C (PKC) also activate the rise in F-actin, although they have no effect on degranulation by themselves. The actin response which can be stimulated by the PKC activators can also be blocked by protein kinase inhibitors indicating that the PMA- and OAG-induced response is probably through activation of a protein kinase. Depletion of PKC activity through long term (20 h) exposure of RBL cells to PMA, also inhibited the F-actin response when the cells were stimulated with either multivalent antigen or OAG. External Ca++, which is an absolute requirement for degranulation, is not necessary for the rise in F-actin, but may modulate the response. Furthermore, ionomycin, which induces a large Ca++ influx, does not stimulate the F-actin increase even at doses that cause degranulation. These results suggest that activation of a protein kinase, such as PKC, may be responsible for signaling the polymerization of actin in RBL cells and that a rise in intracellular Ca++ is neither necessary nor sufficient for this response.
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PMID:Regulation of the antigen-induced F-actin response in rat basophilic leukemia cells by protein kinase C. 182 60

In the 2H3 subline of rat basophilic leukemia cells (RBL-2H3), IgE receptor cross-linking stimulates a signal transduction pathway that leads to the secretion of histamine, serotonin, and other inflammatory mediators; the assembly of F-actin; and the transformation of the cell surface from a microvillous to a lamellar or ruffled architecture. We report here that 20 h incubation of RBL-2H3 cells with 10 microM lovastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG CoA reductase), inhibits both the secretory and morphologic responses to IgE receptor cross-linking. Ag-induced Ca2+ mobilization, determined from the influx and efflux of 45Ca2+, and Ag-induced 1,4,5-inositol trisphosphate production are also inhibited in lovastatin-treated RBL-2H3 cells. Under the same conditions, lovastatin does not alter cell proliferation or IgE receptor expression, and it causes only a small impairment of responses initiated by drugs that bypass the earliest steps in the receptor-activated transduction pathway (ionomycin-induced secretion and PMA-induced membrane ruffling). Receptor-mediated Ca2+ mobilization, secretion, and ruffling are all restored by 0.5- to 4-h incubation of lovastatin-treated cells with mevalonic acid, the product of HMG CoA reductase and the first committed intermediate of the isoprenoid biosynthetic pathway. In contrast, dolichol and cholesterol, which are synthesized from products of the isoprenoid pathway, do not restore receptor-activated responses. These data implicate an isoprenoid pathway intermediate in an early step in the IgE receptor-activated signal-transduction sequence. We postulate that this intermediate is required for a newly described post-translational modification of proteins, their post-synthetic isoprenylation. The substrates for this modification include the ras family of GTP-binding proteins and the gamma subunits of the heterotrimeric guanine nucleotide-binding protein.
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PMID:Role of isoprenoid metabolism in IgE receptor-mediated signal transduction. 182 87


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