scholarly journals The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 260-268
Author(s):  
I Graziadei ◽  
S Gaggl ◽  
R Kaserbacher ◽  
H Braunsteiner ◽  
W Vogel
Keyword(s):  
Chronic Disease ◽  
Progenitor Cells ◽  
Acute Phase ◽  
Iron Metabolism ◽  
Acute Phase Protein ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Phase Protein ◽  
Alpha 1 Antitrypsin ◽  
Dose Dependent

We have previously shown that the hepatic acute-phase protein alpha 1- antitrypsin (alpha 1-AT) inhibits transferrin (tf) binding to its receptor (tfR) of human placental membranes. To evaluate the possibility that this interaction can explain the pathophysiology of the changes in iron metabolism in the course of chronic disease, subsequently leading to anemia in chronic disease (ACD), we examined the effect of alpha 1-AT on cells of the erythroid cell line. alpha 1- AT completely prevented tf binding to tfR on K562 human erythroleukemic cells and on reticulocytes. This inhibitory potency was dose-dependent and competitive, as proved in equilibrium saturation and kinetic studies. The cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha showed no such effect. Internalization of the tf-tfR complex was inhibited with alpha 1-AT in a dose-dependent manner. Furthermore, alpha 1-AT profoundly reduced the growth of K562 cells as well as their proliferation, albeit to a lesser degree. Growth of early erythroid progenitor cells (burst-forming units-erythroid) was significantly suppressed by alpha 1-AT, but no effect on the growth of late erythroid progenitor cells (colony-forming units-erythroid) was detected. These inhibitions of alpha 1-AT were seen in high physiologic concentrations attained in the course of acute-phase situations. These data show that alpha 1-AT might be a mediator of the changes in iron metabolism that are characteristic of clinical findings in the course of ACD.

scholarly journals The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 260-268 ◽  
Author(s):  
I Graziadei ◽  
S Gaggl ◽  
R Kaserbacher ◽  
H Braunsteiner ◽  
W Vogel
Keyword(s):  
Chronic Disease ◽  
Progenitor Cells ◽  
Acute Phase ◽  
Iron Metabolism ◽  
Acute Phase Protein ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Phase Protein ◽  
Alpha 1 Antitrypsin ◽  
Dose Dependent

Abstract We have previously shown that the hepatic acute-phase protein alpha 1- antitrypsin (alpha 1-AT) inhibits transferrin (tf) binding to its receptor (tfR) of human placental membranes. To evaluate the possibility that this interaction can explain the pathophysiology of the changes in iron metabolism in the course of chronic disease, subsequently leading to anemia in chronic disease (ACD), we examined the effect of alpha 1-AT on cells of the erythroid cell line. alpha 1- AT completely prevented tf binding to tfR on K562 human erythroleukemic cells and on reticulocytes. This inhibitory potency was dose-dependent and competitive, as proved in equilibrium saturation and kinetic studies. The cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha showed no such effect. Internalization of the tf-tfR complex was inhibited with alpha 1-AT in a dose-dependent manner. Furthermore, alpha 1-AT profoundly reduced the growth of K562 cells as well as their proliferation, albeit to a lesser degree. Growth of early erythroid progenitor cells (burst-forming units-erythroid) was significantly suppressed by alpha 1-AT, but no effect on the growth of late erythroid progenitor cells (colony-forming units-erythroid) was detected. These inhibitions of alpha 1-AT were seen in high physiologic concentrations attained in the course of acute-phase situations. These data show that alpha 1-AT might be a mediator of the changes in iron metabolism that are characteristic of clinical findings in the course of ACD.

scholarly journals A role for calmodulin in the growth of human hematopoietic progenitor cells

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1446-1454 ◽  
Author(s):  
N Katayama ◽  
M Nishikawa ◽  
F Komada ◽  
N Minami ◽  
S Shirakawa
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Hematopoietic Progenitor Cells ◽  
Dependent Manner ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Gm Csf ◽  
Erythroid Progenitor Cells ◽  
Dependent Inhibition ◽  
Dose Dependent

Abstract A possible role for calmodulin in the colony growth of human hematopoietic progenitor cells was investigated using pharmacologic approaches. We obtained evidence for a dose-dependent inhibition of colony formation of myeloid progenitor cells (CFU-C) stimulated by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte CSF (G-CSF) by three calmodulin antagonists, N- (6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), N- (4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13), and trifluoperazine. Chlorine-deficient analogs of W-7 and W-13, with a lower affinity for calmodulin, did not inhibit the growth of CFU-C colonies. W-7, W-13, and trifluoperazine inhibited the colony formation of immature erythroid progenitor cells (BFU-E) stimulated by IL-3 plus erythropoietin (Ep) or GM-CSF plus Ep, in a dose-dependent manner, while they did not affect the colony formation of mature erythroid progenitor cells (CFU-E) induced by Ep. W-7, W-13, and trifluoperazine also led to a dose-dependent inhibition of GM-CSF-induced colony formation of KG-1 cells. Calmodulin-dependent kinase activity derived from the KG-1 cells was inhibited by these three calmodulin antagonists in a dose-dependent manner. These data suggest that calmodulin may play an important regulatory role via a common process in the growth of hematopoietic progenitor cells stimulated by IL-3, GM-CSF, and G-CSF. Mechanisms related to the growth signal of Ep apparently are not associated with calmodulin-mediated systems.

Prohepcidin in pregnancy: Acute phase protein, marker of iron metabolism, or both?

2008 ◽  
Vol 140 (2) ◽  
pp. 293-294 ◽  
Author(s):  
Leszek Rams ◽  
Lena-Drozdowska-Rams ◽  
Jacek Malyszko ◽  
Krystyna Pawlak ◽  
Jolanta Malyszko
Keyword(s):  
Acute Phase ◽  
Iron Metabolism ◽  
Acute Phase Protein ◽  
Protein Marker ◽  
Phase Protein ◽  
In Pregnancy

scholarly journals A role for calmodulin in the growth of human hematopoietic progenitor cells

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1446-1454
Author(s):  
N Katayama ◽  
M Nishikawa ◽  
F Komada ◽  
N Minami ◽  
S Shirakawa
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Hematopoietic Progenitor Cells ◽  
Dependent Manner ◽  
Hematopoietic Progenitor ◽  
Erythroid Progenitor ◽  
Gm Csf ◽  
Erythroid Progenitor Cells ◽  
Dependent Inhibition ◽  
Dose Dependent

A possible role for calmodulin in the colony growth of human hematopoietic progenitor cells was investigated using pharmacologic approaches. We obtained evidence for a dose-dependent inhibition of colony formation of myeloid progenitor cells (CFU-C) stimulated by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte CSF (G-CSF) by three calmodulin antagonists, N- (6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), N- (4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13), and trifluoperazine. Chlorine-deficient analogs of W-7 and W-13, with a lower affinity for calmodulin, did not inhibit the growth of CFU-C colonies. W-7, W-13, and trifluoperazine inhibited the colony formation of immature erythroid progenitor cells (BFU-E) stimulated by IL-3 plus erythropoietin (Ep) or GM-CSF plus Ep, in a dose-dependent manner, while they did not affect the colony formation of mature erythroid progenitor cells (CFU-E) induced by Ep. W-7, W-13, and trifluoperazine also led to a dose-dependent inhibition of GM-CSF-induced colony formation of KG-1 cells. Calmodulin-dependent kinase activity derived from the KG-1 cells was inhibited by these three calmodulin antagonists in a dose-dependent manner. These data suggest that calmodulin may play an important regulatory role via a common process in the growth of hematopoietic progenitor cells stimulated by IL-3, GM-CSF, and G-CSF. Mechanisms related to the growth signal of Ep apparently are not associated with calmodulin-mediated systems.

scholarly journals Regulation of Cellular Iron Metabolism by Erythropoietin: Activation of Iron-Regulatory Protein and Upregulation of Transferrin Receptor Expression in Erythroid Cells

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 680-687 ◽  
Author(s):  
Günter Weiss ◽  
Tracey Houston ◽  
Stefan Kastner ◽  
Karin Jöhrer ◽  
Kurt Grünewald ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Regulatory Protein ◽  
Receptor Expression ◽  
General Mechanism ◽  
Iron Regulatory Protein ◽  
Erythroid Progenitor ◽  
Cellular Iron ◽  
Erythroid Progenitor Cells

Abstract Erythropoietin (Epo) is the central regulator of red blood cell production and acts primarily by inducing proliferation and differentiation of erythroid progenitor cells. Because a sufficient supply of iron is a prerequisite for erythroid proliferation and hemoglobin synthesis, we have investigated whether Epo can regulate cellular iron metabolism. We present here a novel biologic function of Epo, namely as a potential modulator of cellular iron homeostasis. We show that, in human (K562) and murine erythroleukemic cells (MEL), Epo enhances the binding affinity of iron-regulatory protein (IRP)-1, the central regulator of cellular iron metabolism, to specific RNA stem-loop structures, known as iron-responsive elements (IREs). Activation of IRP-1 by Epo is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and MEL, enhanced cell surface expression of trf-recs, and increased uptake of iron into cells. These findings are in agreement with the well-established mechanism whereby high-affinity binding of IRPs to IREs stabilizes trf-rec mRNA by protecting it from degradation by a specific RNase. The effects of Epo on IRE-binding of IRPs were not observed in human myelomonocytic cells (THP-1), which indicates that this response to Epo is not a general mechanism observed in all cells but is likely to be erythroid-specific. Our results provide evidence for a direct functional connection between Epo biology and iron metabolism by which Epo increases iron uptake into erythroid progenitor cells via posttranscriptional induction of trf-rec expression. Our data suggest that sequential administration of Epo and iron might improve the response to Epo therapy in some anemias.

Lyn Kinase Supports Primary Erythroid Progenitor Cell Development.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1622-1622
Author(s):  
Vinit Karur ◽  
Bethany Vincent ◽  
Clifford Lowell ◽  
Don M. Wojchowski
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Cell Development ◽  
Wild Type ◽  
Erythroid Progenitor ◽  
Epo Receptor ◽  
Erythroid Progenitor Cell ◽  
Lyn Kinase ◽  
Erythroid Progenitor Cells ◽  
Dose Dependent

Abstract Several lines of investigation have implicated Lyn as an important positive effector of red cell development: Deregulated Src kinases promote erythroleukemia, and Lyn is the predominant Src kinase of erythroid cells; as critical erythropoietic factors, Kit and the Epo receptor each stimulate Lyn kinase; and in an insightful set of investigations in J2E cells, Lyn has been shown to be required for Epo-dependent late erythroid development. Based on these considerations, adult bone marrow-derived primary erythroid progenitor cells from Lyn −/− mice presently were assessed for their ex vivo growth, survival and differentiation potentials. Lyn −/− erythroid progenitors expanded efficiently in serum-free media, and showed essentially wild-type Epo dose-dependent proliferative responsiveness. When transferred to BSA/insulin/transferrin differentiation medium, however, Lyn −/− erythroid progenitor cells clearly faltered in their development to Ter119-high, CD71-low erythroblasts. For these Lyn −/− cells, annexin-V binding studies revealed that this defect was associated, in part, with a stage-specific loss in survival potential. Interestingly, however, this defect was not Epo-dose dependent. In addition, MACS-isolated Kit-positive early erythroid progenitor cells prepared from Lyn −/− mice (unlike preparations from wild-type mice) failed to support synergistic effects of SCF-plus-Epo in 3HdT incorporation assays. In response to phenylhydrazine, Lyn −/− mice exhibited expanded erythroid progenitor cell pools (including BFUe and CFUe), and this hyper-expansion may occur in response to the compromised survival of late Lyn −/− erythroblasts. Analyses of pp60-Src expression revealed elevated levels of activated PY416-Src specifically in Lyn −/− EPC, a finding that is consistent with the activation of apparent compensatory mechanisms. In contrast, no significant changes in the levels of GATA1 or other assessed erythroid defining factors were detected. In response to phenylhydrazine, Lyn −/− mice showed ≥2-fold enhanced splenomegaly, as well as enhanced frequencies of BFUe, CFUe and Ter119(+) cells. Overall, these studies in primary erythroid progenitor cells from Lyn −/− mice reveal a previously undiscovered positive role for Lyn as a late-stage specific positive effector of erythroid cell survival, and regulator of Epo receptor and Kit co-signaling.

Antithrombin Acts as a Negative Acute Phase Protein as Established with Studies on HepG2 Cells and in Baboons

1997 ◽  
Vol 78 (03) ◽  
pp. 1088-1092 ◽  
Author(s):  
R W L M Niessen ◽  
R J Lamping ◽  
P M Jansen ◽  
M H Prins ◽  
M Peters ◽  
...  
Keyword(s):  
Acute Phase ◽  
Plasma Levels ◽  
Hepg2 Cells ◽  
Acute Phase Protein ◽  
Major Surgery ◽  
Maximum Effect ◽  
Hepatoma Cell Line ◽  
Fibrinogen Concentration ◽  
Phase Protein ◽  
Dose Dependent

SummaryPatients with sepsis or after major surgery have decreased plasma levels of the anticoagulant protein antithrombin. In such patients elevated levels of interleukin-6 (IL-6) are present and this interleukin is known to induce positive and negative acute phase responses. To investigate the possibility that antithrombin acts as a negative acute phase response-protein we performed studies on the human hepatoma cell line HepG2 in vitro and baboons in vivo. HepG2 cells were treated with recombinant human IL-6, ILß3, or combinations of the latter two, and tested for production of antithrombin, fibrinogen and prealbumin (transthyretin). This treatment resulted in a dose dependent increase in fibrinogen concentration (with a maximum effect of 2.8-2.9-fold) and a dose dependent decrease in prealbumin (with a maximum effect of 0.6-0.7-fold) and antithrombin concentrations (with a maximum effect of 0.6-0.8-fold). Simultaneous treatment of the HepG2 cells with IL-6 (1,000 pg/ml or 2,500 pg/ml) and IL-1β (25 pg/ml), provided more extensively decreased prealbumin (0.8 and 0.6-fold, respectively) and antithrombin concentration (0.7 and 0.6-fold, respectively) compared to the single interleukin treatment at these concentrations. Baboons treated with 2 µg IL-6 · kg body-weight-1 · day1 showed increased plasma CRP levels (59-fold, p <0.05) and decreased prealbumin (0.9-fold, p <0.05) and antithrombin (0.8-fold, p <0.05) plasma levels, without evidence for coagulation activation. Our results indicate that antithrombin acts as a negative acute phase protein, which may contribute to the decreased antithrombin plasma levels observed after major surgery or in sepsis.

Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3147-3153 ◽  
Author(s):  
Ke Li ◽  
Madhu P. Menon ◽  
Vinit G. Karur ◽  
Shailaja Hegde ◽  
Don M. Wojchowski
Keyword(s):  
Progenitor Cells ◽  
Embryonic Stem ◽  
Janus Kinase ◽  
Compensatory Mechanisms ◽  
Erythroid Progenitor ◽  
Stress Erythropoiesis ◽  
Erythroid Progenitor Cells ◽  
Erythroid Development ◽  
Dose Dependent

Abstract Signals provided by the erythropoieitin receptor (EpoR) are required for erythroid development beyond the erythroid colony-forming unit (CFU-e) stage and are propagated via the EpoR-tethered Janus kinase, JAK2. JAK2 functions, in part, to phosphorylate 8 conserved EpoR phosphotyrosine (PY) sites for the binding of a diverse set of signaling factors. However, recent studies in transgenic and knock-in mice have demonstrated substantial bioactivity for PY-null EpoR forms. Presently, the activities of a PY-null EpoR-HM form in primary progenitor cells from knock-in mice were further assessed using optimized Epo dose-dependent proliferation, survival, and differentiation assays. As compared with the wild-type (wt)–EpoR, EpoR-HM activity was compromised several-fold in each context when Epo was limited to physiologic concentrations. Possible compensatory increases in serum growth factor levels also were investigated, and as assayed using embryonic stem (ES) cell–derived erythroid G1E2 cells, activities in serum from EpoR-HM mice were substantially elevated. In addition, when challenged with phenylhydrazine-induced anemia, EpoR-HM mice failed to respond with efficient splenic stress erythropoiesis. Thus, the function of this JAK2-coupled but minimal PY-null EpoR-HM form appears to be attenuated in several contexts and to be assisted in vivo by compensatory mechanisms. Roles normally played by EpoR PY sites and distal domains therefore should receive continued attention.

Sign in / Sign up

Export Citation Format

Share Document