scholarly journals Hematopoietic progenitors and interleukin-3-dependent cell lines synthesize histamine in response to calcium ionophore

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3161-3169 ◽  
Author(s):  
M Dy ◽  
A Arnould ◽  
FM Lemoine ◽  
F Machavoine ◽  
H Ziltener ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mrna Expression ◽  
Cell Lines ◽  
Histidine Decarboxylase ◽  
Calcium Ionophore ◽  
Ionophore A23187 ◽  
Hematopoietic Progenitors ◽  
Histamine Synthesis ◽  
Histamine Production ◽  
Dependent Cell

The calcium ionophore A23187 promotes histamine synthesis in murine bone marrow cells by increasing the expression of mRNA encoding histidine decarboxylase (HDC), the histamine-forming enzyme. The cells responsible for this biological activity copurify with hematopoietic progenitors in terms of density, light scatter characteristics, and rhodamine retention, similar to interleukin (IL) 3-induced histamine- producing cells. Yet, the effect of calcium ionophore is not mediated by IL-3. The most purified rhodamine-bright bone marrow subset contains 80% cells that respond to calcium ionophore by increased HDC mRNA expression. This high frequency makes the involvement of one particular progenitor subset in histamine synthesis unlikely. The finding that all IL-3-dependent cell lines tested so far exhibit increased histamine production and HDC mRNA expression in response to calcium influx lends further support to this notion. Cell lines requiring other growth factors or proliferating spontaneously lack this ability. Finally, it should be noted that IL-3-dependent cell lines do not produce histamine in response to their growth factor. It might, therefore, be suggested that the pathway transducing the signal for increased histamine synthesis after IL-3 receptor binding in normal hematopoietic progenitors is modified in these cell lines.

scholarly journals Aggregated IgE mimic interleukin-3-induced histamine synthesis by murine hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1098-1107
Author(s):  
F Salachas ◽  
E Schneider ◽  
FM Lemoine ◽  
B Lebel ◽  
M Daeron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histidine Decarboxylase ◽  
Bone Marrow Cells ◽  
Specific Inhibitor ◽  
Target Cells ◽  
Hematopoietic Progenitors ◽  
Interleukin 3 ◽  
Histamine Synthesis ◽  
Histamine Production ◽  
Marrow Cells

Similar to interleukin-3 (IL-3), IgE acts on murine bone marrow cells by inducing histamine production. This effect does not result from degranulation of histamine-containing cells, but from histamine synthesis, as assessed by the following findings. (1) The histamine content of freshly isolated bone marrow cells is too low to account for the increase in extracellular histamine levels. (2) Neither IL-3 nor IgE induced histamine production in the presence of the specific inhibitor of histidine decarboxylase (HDC), the histamine-forming enzyme. (3) Both the enzymatic activity and the mRNA expression of HDC were enhanced in response to IL-3 or IgE. Artificial aggregation or formation of IgE immune complexes augmented ther effect on histamine synthesis, indicating that the aggregated form is responsible for this biologic activity. Yet, it is apparently not mediated by Fc epsilon RI because their cross-linkage by dinitrophenyl bovine serum albumin after presensitization with IgE did not induce histamine production by hematopoietic progenitors. Among other aggregated isotypes tested, only IgG2a and, to a lesser extent, IgG1 had a consistent but lower effect, whereas IgM and IgA were completely inactive. The target cells of IL-3 and IgE in terms of histamine synthesis do not belong to mature bone marrow populations, especially mast cells. They copurify with hematopoietic progenitors in the low-density layers of a discontinuous Ficoll gradient where they represent around 5% of the cells, as determined by in situ hybridization. This percentage remained the same, regardless of whether the cells were stimulated by IgE or IL-3 alone or by a combination of both, suggesting a common responder cell. In accordance with this notion, histamine-producing cells could not be distinguished from each other on the basis of density, size and internal structure, or rhodamine (Rh) retention. Finally, the effect of IgE is not caused by the induction of IL-3 because anti-IL-3 antibodies did not abrogate the effect of IgE.

scholarly journals Aggregated IgE mimic interleukin-3-induced histamine synthesis by murine hematopoietic progenitors

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1098-1107 ◽  
Author(s):  
F Salachas ◽  
E Schneider ◽  
FM Lemoine ◽  
B Lebel ◽  
M Daeron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histidine Decarboxylase ◽  
Bone Marrow Cells ◽  
Specific Inhibitor ◽  
Target Cells ◽  
Hematopoietic Progenitors ◽  
Interleukin 3 ◽  
Histamine Synthesis ◽  
Histamine Production ◽  
Marrow Cells

Abstract Similar to interleukin-3 (IL-3), IgE acts on murine bone marrow cells by inducing histamine production. This effect does not result from degranulation of histamine-containing cells, but from histamine synthesis, as assessed by the following findings. (1) The histamine content of freshly isolated bone marrow cells is too low to account for the increase in extracellular histamine levels. (2) Neither IL-3 nor IgE induced histamine production in the presence of the specific inhibitor of histidine decarboxylase (HDC), the histamine-forming enzyme. (3) Both the enzymatic activity and the mRNA expression of HDC were enhanced in response to IL-3 or IgE. Artificial aggregation or formation of IgE immune complexes augmented ther effect on histamine synthesis, indicating that the aggregated form is responsible for this biologic activity. Yet, it is apparently not mediated by Fc epsilon RI because their cross-linkage by dinitrophenyl bovine serum albumin after presensitization with IgE did not induce histamine production by hematopoietic progenitors. Among other aggregated isotypes tested, only IgG2a and, to a lesser extent, IgG1 had a consistent but lower effect, whereas IgM and IgA were completely inactive. The target cells of IL-3 and IgE in terms of histamine synthesis do not belong to mature bone marrow populations, especially mast cells. They copurify with hematopoietic progenitors in the low-density layers of a discontinuous Ficoll gradient where they represent around 5% of the cells, as determined by in situ hybridization. This percentage remained the same, regardless of whether the cells were stimulated by IgE or IL-3 alone or by a combination of both, suggesting a common responder cell. In accordance with this notion, histamine-producing cells could not be distinguished from each other on the basis of density, size and internal structure, or rhodamine (Rh) retention. Finally, the effect of IgE is not caused by the induction of IL-3 because anti-IL-3 antibodies did not abrogate the effect of IgE.

scholarly journals Calcium ionophore but not phorbol ester promotes eicosanoids release by proliferating interleukin-3-dependent bone marrow cells

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1586-1592 ◽  
Author(s):  
Y Shibata ◽  
PG McCaffrey ◽  
H Sato ◽  
Y Oghiso
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Phorbol Ester ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
Calcium Ionophore ◽  
Mouse Bone Marrow ◽  
Ionophore A23187 ◽  
Interleukin 3 ◽  
Marrow Cells

Abstract Eicosanoid release during multilineage hematopoiesis was assessed using freshly isolated mouse bone marrow cells cultured in the presence of interleukin-3 (IL-3) (10% WEHI-3 culture-conditioned medium). Cells that could release prostaglandin E2 (PGE2) when stimulated with calcium ionophore A23187, but not with phorbol ester (PMA), appeared within 4 days. The cells harvested on day 10 released 42 ng of PGE2/10(6) cells/mL after A23187 stimulation. Leukotriene B4 (LTB4) (4 ng/mL) was also detected after A23187 stimulation, but there was no detectable LTC4 (less than 0.5 ng/mL). Nonadherent bone marrow cells were isolated from 28-day cultures and cloned. All clones were strongly IL-3- dependent. Although other growth factors such as granulocyte colony- stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and CSF-1 failed to promote survival or support proliferation of the cells, three clones (11–1-A6, 3–2-D5, and 11–1-A1) showed significant increases in 3H-thymidine incorporation, respectively, after PMA treatment for 24 hours. Surviving cells displayed dominantly myeloid type morphology and phenotypic characteristics. The data suggest that IL-3 is important in the formation of PGE2-producing cells. In contrast to many macrophages (MO), neither the IL-3-dependent cell lines nor the IL-3-cultured bone marrow cells released significant amounts of PGE2 when stimulated with PMA or IL-3, although PMA and IL-3 both induced translocation of protein kinase C (PKC) to the membrane fraction. The lack of production of PGE2 and other eicosanoids by the PMA- and IL-3- stimulated cell lines was confirmed by measuring the release of 3H- arachidonic acid. The data suggest that in IL-3-dependent bone marrow cell lines the activation of eicosanoid metabolism requires elevated cellular Ca2+; PKC activation alone does not appear to be a sufficient stimulus.

scholarly journals Calcium ionophore but not phorbol ester promotes eicosanoids release by proliferating interleukin-3-dependent bone marrow cells

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1586-1592
Author(s):  
Y Shibata ◽  
PG McCaffrey ◽  
H Sato ◽  
Y Oghiso
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Phorbol Ester ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
Calcium Ionophore ◽  
Mouse Bone Marrow ◽  
Ionophore A23187 ◽  
Interleukin 3 ◽  
Marrow Cells

Eicosanoid release during multilineage hematopoiesis was assessed using freshly isolated mouse bone marrow cells cultured in the presence of interleukin-3 (IL-3) (10% WEHI-3 culture-conditioned medium). Cells that could release prostaglandin E2 (PGE2) when stimulated with calcium ionophore A23187, but not with phorbol ester (PMA), appeared within 4 days. The cells harvested on day 10 released 42 ng of PGE2/10(6) cells/mL after A23187 stimulation. Leukotriene B4 (LTB4) (4 ng/mL) was also detected after A23187 stimulation, but there was no detectable LTC4 (less than 0.5 ng/mL). Nonadherent bone marrow cells were isolated from 28-day cultures and cloned. All clones were strongly IL-3- dependent. Although other growth factors such as granulocyte colony- stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and CSF-1 failed to promote survival or support proliferation of the cells, three clones (11–1-A6, 3–2-D5, and 11–1-A1) showed significant increases in 3H-thymidine incorporation, respectively, after PMA treatment for 24 hours. Surviving cells displayed dominantly myeloid type morphology and phenotypic characteristics. The data suggest that IL-3 is important in the formation of PGE2-producing cells. In contrast to many macrophages (MO), neither the IL-3-dependent cell lines nor the IL-3-cultured bone marrow cells released significant amounts of PGE2 when stimulated with PMA or IL-3, although PMA and IL-3 both induced translocation of protein kinase C (PKC) to the membrane fraction. The lack of production of PGE2 and other eicosanoids by the PMA- and IL-3- stimulated cell lines was confirmed by measuring the release of 3H- arachidonic acid. The data suggest that in IL-3-dependent bone marrow cell lines the activation of eicosanoid metabolism requires elevated cellular Ca2+; PKC activation alone does not appear to be a sufficient stimulus.

Implication of HIF-1α but Not HIF-2α in the Hypoxic Response of Human Hematopoietic Progenitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4154-4154
Author(s):  
Yanyan Zhang ◽  
Adlen Foudi ◽  
Magali Berthebaud ◽  
Dorothee Buet ◽  
Peggy Jarrier ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Hematopoietic Cells ◽  
Receptor Expression ◽  
Metabolic Adaptation ◽  
Protein Accumulation ◽  
Mrna Levels ◽  
Hematopoietic Progenitors ◽  
Cd34 Cells ◽  
Cxcr4 Mrna

Abstract Maturing hematopoietic cells are exposed to hypoxia as they develop and migrate within the bone marrow microenvironment. Previous studies using non hematopoietic cell lines and monocytes showed that CXCR4 is strongly induced by hypoxia but little is known on the regulation of CXCR4 by hypoxia in the other hematopoietic cells and during hematopoietic development. We analyzed the expression and regulation of hypoxia-inducible transcription factor-1a (HIF1a) and 2a (HIF2a), the master regulators of metabolic adaptation to hypoxia, during hematopoiesis. Real time quantitative RT-PCR showed that HIF-1a mRNA was present on all the non hematopoietic and hematopoietic cells lines including HL-60, HEL, TF1, K562, KG1, U937, Jurkat and Mo7e. In contrast, HIF-2a mRNA expression was variable among the cell lines and was detected only at very low level in some cells such as KG1, Jurkat and HEL. Hypoxia exposure rapidly induced VEGF mRNA expression in the cells that expressed HIF-1a mRNA and exhibited HIF-1a protein accumulation. Interestingly, CXCR4 induction was observed only in the cells that exhibit significant expression of HIF-2a mRNA and HIF-2a protein accumulation. A strong correlation between HIF-2a mRNA levels and the induction of CXCR4 mRNA expression by hypoxia was found. Human CD34+ cells also expressed high levels of HIF-1a mRNA, whereas HIF-2a mRNA was barely detected. Interestingly, as observed for several myeloid cell lines, CD34+ cells exhibited a strong induction of VEGF expression in response to hypoxia and hypoxia mimetic agents cobalt chloride and desferrrioxamine whereas CXCR4 receptor expression was not induced suggesting that CXCR4 mRNA induction is related to the expression of HIF-2a. Altogether these data indicated that the hypoxic responses of human hematopoietic progenitors are independent of HIF-2a. Moreover, they establish that CXCR4 regulation by hypoxia is linked to HIF-2a protein expression.

scholarly journals A role for intracellular histamine in collagen-induced platelet aggregation

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 407-414 ◽  
Author(s):  
SP Saxena ◽  
A McNicol ◽  
LJ Brandes ◽  
AB Becker ◽  
JM Gerrard
Keyword(s):  
Platelet Aggregation ◽  
Histidine Decarboxylase ◽  
Histamine Receptor ◽  
Cyclooxygenase Inhibitors ◽  
Histamine Synthesis ◽  
Serotonin Secretion ◽  
Histamine Production ◽  
Thromboxane Production ◽  
Induced Aggregation

Abstract We previously demonstrated that newly formed intracellular histamine mediates platelet aggregation in response to phorbol-12-myristate-13- acetate (PMA). We now report further investigations of the role of histamine during physiological activation of platelets by collagen. Platelets stirred with collagen produced histamine; the rise in histamine precedes the onset of aggregation. The dose response for collagen stimulation of histamine synthesis and platelet aggregation is similar. Inhibitors of histidine decarboxylase (HDC) block both aggregation and histamine synthesis in parallel. Histamine production is not dependent on aggregation; both the intracellular histamine receptor antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine- HCl (DPPE), and the cyclooxygenase inhibitors, aspirin and indomethacin, inhibit collagen-induced aggregation but not histamine synthesis. DPPE also inhibits collagen-induced serotonin secretion and thromboxane production. The effects of DPPE and HDC inhibitors are significantly reversed by the addition of histamine (0.1 to 10 mumol/L) to saponin-permeabilized platelets, though histamine alone has no pro- aggregatory effects. The results suggest that newly synthesized intracellular histamine has a role in collagen-induced platelet activation and that it may act to promote the generation of thromboxane and the secretion responses of platelet granules.

Upregulation of MMP-2 & 9 by Co-Culture of Human Myeloma Cell Lines and Endothelial Cells May Be Responsible for Protection Against Cytotoxic Drugs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5080-5080
Author(s):  
Shankaranarayana Paneesha ◽  
Raghu Adya ◽  
Hemali Khanji ◽  
Ed Leung ◽  
C. Vijayasekar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Human Myeloma Cell

Abstract Multiple myeloma is a clonal lymphoproliferative disorder characterised by the proliferation of plasma cells in the bone marrow. Inspite of good initial response, it is associated with universal relapse. We hypothesise this is due to sanctuary provided to myeloma cells by the endothelium. Matrix metalloproteinases (MMPs) are shown play a role in cell growth, invasion, angiogenesis, metastasis and bone degradation. We show here the protection offered by endothelial cells to human myeloma cell lines in in-vitro co-culture with upregulation of MMP-2 & 9 and the role of GM6001 MMP inhibitor (Ilomastat) in overcoming this protection. Human myeloma cell lines (H929, RPMI 8226, U266 & JJN3) with or without endothelial cells (human umbilical vein endothelial cells and EaHy 926 cell line) in-vitro co-culture were treated with melphalan, dexamethasone, arsenic trioxide and Ilomastat. Cytotoxicity/proliferation were assessed by the alamarBlue™ assay (Serotec) and validated by Annexin V-FITC apoptosis detection Kit (Calbiochem) and BrDU proliferation assay (BD Pharmingen™). Gelatin Zymography was used to demonstrate activity of MMP-2 & 9 in the supernatant. MMP-2 and 9 mRNA expression was quantified by Real Time Quantitative PCR (ROCHE). Co-culture of human myeloma cell lines with endothelial cells lead to increase in the proliferation of myeloma cell lines and also protected them from the cytotoxicity of chemotherapeutic agents. MMP-2 & 9 activity was upregulated by the co-culture. MMP-2 mRNA expression in human myeloma cell lines increased following 4 hr co-culture. Treatments with Ilomastat lead to the suppression of proliferation in co-culture in a dose dependent manner, associated with a reduction of MMP-2 and 9 activity. Our study shows endothelial cells offer protection to human myeloma cell lines in the presence of cytotoxic agents. This may result in the sanctuary of myeloma cells in bone marrow leading to ultimate relapse of disease. Our study also demonstrates the upregulation of MMP-2 and 9 by co-culture and increased cytotoxicity achieved by the inhibition of MMPs. Further studies are needed to determine the exact role of MMPs in myeloma biology as MMP inhibition may be an interesting therapeutic target and help in averting relapse in multiple myeloma.

Hypoxia Drives AML Proliferation in the Bone Marrow Microenvironment Via Macrophage Inhibitory Factor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1721-1721
Author(s):  
Amina M Abdul-Aziz ◽  
Manar S Shafat ◽  
Lyubov Zaitseva ◽  
Matthew J Lawes ◽  
Stuart A Rushworth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Mrna Expression ◽  
Cell Lines ◽  
Bone Marrow Microenvironment ◽  
Inhibitory Factor ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hypoxic Conditions

Abstract Introduction Hypoxia is an important component of the bone marrow microenvironment and the hematopoietic stem cell niche. Studies have shown that hypoxia contributes to the development and maintenance of acute myeloid leukemia (AML) cells within the bone marrow microenvironment. Hypoxia is principally maintained by members of the hypoxia-inducible factor (HIF), in particular HIF1a and its target genes, including MIF. We have previously shown that AML cells express constitutively high macrophage migration inhibitory factor (MIF) which drives IL-8 expression by the BM-MSC which in turn supports AML cell survival and proliferation. The aim of the present study is to determine if there is a connection between the role of hypoxia in regulating AML survival and MIF survival signals. Furthermore we investigate the role BM-MSC in regulating the hypoxic response. Methods Primary AML and BM-MSC were isolated from AML patients following informed consent and under approval from the UK National Research Ethics Service (LRCEref07/H0310/146). AML cell lines and primary AML blasts were cultured under normoxic (20% oxygen) or hypoxic conditions (1% oxygen) for 4 - 24 hours, mRNA expression of MIF, HIF1a, VEGF and IL-8 were determined by RT-PCR. MIF and IL-8 protein was determined using target specific ELISA. HIF1a protein expression was determined by western blotting. Hypoxia-mimetic agents, cobalt chloride (CoCl2) and desferrioxamine (DFO) were used. Cell proliferation was determines using CellTiter Glo and trypan blue exclusion. CFU-assays were performed using complete methylcellulose media. Results To determine If MIF is regulated by HIF1a in AML cells, we mimicked hypoxic conditions using CoCl2 and DFO in AML cells. Both CoCl2 and DFO upregulate MIF transcription and protein expression in OCI-AML3 cell lines and in primary AML blasts. Moreover, hypoxia increases both MIF mRNA expression and MIF chemokine expression compared to normoxic conditions. Lentiviral mediated knockdown of MIF in AML cells show significantly reduced cell proliferation and colony formation in methylcellulose media. Recombinant MIF induced interleukin-8 in AML blasts and the MIF inhibitor blocked MIF induced IL-8 release. Lentiviral mediated KD of HIF1a decreased MIF expression in human AML cells and a significant reduced their proliferative capacity. Finally we found that hypoxia increased MIF in AML blasts which was further increased when in co-culture with BM-MSC. Conclusions The results reported here suggest that hypoxia significantly affects the expression of the survival cytokine MIF in AML blasts. Furthermore, we show that BM-MSC regulate HIF1a induced MIF expression in AML under hypoxic conditions. We propose this hypoxia regulated HIF1a/MIF axis is essential to blast survival in the bone marrow niche. Disclosures Rushworth: Infinity Pharmaceuticals: Research Funding.

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