scholarly journals S100A4 Regulates Macrophage Chemotaxis

2010 ◽  
Vol 21 (15) ◽  
pp. 2598-2610 ◽  
Author(s):  
Zhong-Hua Li ◽  
Natalya G. Dulyaninova ◽  
Reniqua P. House ◽  
Steven C. Almo ◽  
Anne R. Bresnick
Keyword(s):  
Tumor Metastasis ◽  
Colony Stimulating Factor ◽  
S100 Family ◽  
Macrophage Chemotaxis ◽  
Primary Bone ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Primary Bone Marrow

S100A4, a member of the S100 family of Ca2+-binding proteins, is directly involved in tumor metastasis. In addition to its expression in tumor cells, S100A4 is expressed in normal cells and tissues, including fibroblasts and cells of the immune system. To examine the contribution of S100A4 to normal physiology, we established S100A4-deficient mice by gene targeting. Homozygous S100A4−/−mice are fertile, grow normally and exhibit no overt abnormalities; however, the loss of S100A4 results in impaired recruitment of macrophages to sites of inflammation in vivo. Consistent with these observations, primary bone marrow macrophages (BMMs) derived from S100A4−/−mice display defects in chemotactic motility in vitro. S100A4−/−BMMs form unstable protrusions, overassemble myosin-IIA, and exhibit altered colony-stimulating factor-1 receptor signaling. These studies establish S100A4 as a regulator of physiological macrophage motility and demonstrate that S100A4 mediates macrophage recruitment and chemotaxis in vivo.

Effects of Imatinib Mesylate and Interferon-alpha Combined with Granulocyte Colony-Stimulating Factor on Chronic Myelogenous Leukemia Cells In Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4665-4665
Author(s):  
Shuichi Ota ◽  
Manabu Musashi ◽  
Keiichi Kondo ◽  
Nobuyasu Toyoshima ◽  
Tomomi Toubai ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Interferon Alpha ◽  
Cell Number ◽  
Myelogenous Leukemia ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Primary Bone ◽  
Stimulating Factor ◽  
Primary Bone Marrow

Abstract Aim. In the treatment of patients with chronic myelogenous leukemia (CML), neutropenia is a dose-limiting factor on the combination therapy of imatinib mesylate (STI571) and interferon-alpha. If STI571 combined with interferon-alpha effects on decreasing BCR-ABL-positive cells and granulocyte colony-stimulating factor (G-CSF) has an effect on increasing normal neutrophils, the combination therapy may improve current remission rates in CML. We evaluated in vitro combined effect of STI571, interferon-alpha and G-CSF on primary bone marrow cells from patients with CML in chronic phase (CP). Material and Methods. The primary bone marrow mononuclear cells (BMMNC) from patients with CML-CP were incubated in the medium containing STI571 (1 μM) and/or interferon-alpha (100 U/ml) with or without G-CSF (100 ng/ml). The viability of the cells was evaluated by trypan blue dye exclusion. Apoptosis was detected by the flow cytometry analysis with Annexin V (AV) and propidium iodide (PI) double staining. The colony formation assays of BMMNC were performed by methylcelulose. And then, BCR-ABL and normal cell colony rates were evaluated on14 days. Results. Treatment of BMMNC with STI571 revealed a decrease of cell number in dose-dependent and time-dependent manner. Incubation with STI571 and interferon-alpha for 24 and 48 hours decreased viable cell number by 58% and 39%, respectively. G-CSF did not stimulate the BCR-ABL-expressing cells proliferation in the combination therapy. Cytometry analysis with AV and PI showed about 70–75% of AV-positive cells in the combination therapy and monotherapy. There were no significant differences in apoptosis between STI571 plus G-CSF and interferon-alpha plus G-CSF. Colony formation of BMMNC from patients with CML-CP in combination of STI571 and interferon-alpha was more strongly suppressed than STI571alone, and G-CSF did not abrogate the suppressive effect of the combination therapy. From these observations, it is concluded that combination therapy of STI571 and interferon-alpha with G-CSF can induce apoptosis effectively in BCR-ABL-expressing cells. Conclusion. Obtained data provide an evidence for the effective and safe combination therapy of STI571 and interferon-alpha with G-CSF against CML-CP patients. Although further studies are needed to clarify whether combination therapy really increase normal cells or not, the combined therapy with G-CSF appears not to stimulate leukemic cell proliferation.

Identification of tyrosine 706 in the kinase insert as the major colony-stimulating factor 1 (CSF-1)-stimulated autophosphorylation site in the CSF-1 receptor in a murine macrophage cell line

1990 ◽  
Vol 10 (6) ◽  
pp. 2991-3002
Author(s):  
P van der Geer ◽  
T Hunter
Keyword(s):  
Cell Line ◽  
Murine Macrophage ◽  
Colony Stimulating Factor ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Major Site ◽  
Murine Macrophage Cell Line ◽  
Stimulating Factor

The receptor for colony-stimulating factor 1 (CSF-1) is a ligand-activated protein-tyrosine kinase. It has been shown previously that the CSF-1 receptor is phosphorylated on serine in vivo and that phosphorylation on tyrosine can be induced by stimulation with CSF-1. We studied the phosphorylation of the CSF-1 receptor by using the BAC1.2F5 murine macrophage cell line, which naturally expresses CSF-1 receptors. Two-dimensional tryptic phosphopeptide mapping showed that the CSF-1 receptor is phosphorylated on several different serine residues in vivo. Stimulation with CSF-1 at 37 degrees C resulted in rapid phosphorylation on tyrosine at one major site and one or two minor sites. We identified the major site as Tyr-706. The identity of Tyr-706 was confirmed by mutagenesis. This residue is located within the kinase insert domain. There was no evidence that Tyr-973 (equivalent to Tyr-969 in the human CSF-1 receptor) was phosphorylated following CSF-1 stimulation. When cells were stimulated with CSF-1 at 4 degrees C, additional phosphotyrosine-containing phosphopeptides were detected and the level of phosphorylation of the individual phosphotyrosine-containing phosphopeptides was substantially increased. In addition, we show that CSF-1 receptors are capable of autophosphorylation at six to eight major sites in vitro.

scholarly journals Interleukin-6 and the Granulocyte Colony-Stimulating Factor Receptor Are Major Independent Regulators of Granulopoiesis In Vivo But Are Not Required for Lineage Commitment or Terminal Differentiation

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2583-2590 ◽  
Author(s):  
Fulu Liu ◽  
Jennifer Poursine-Laurent ◽  
Huai Yang Wu ◽  
Daniel C. Link
Keyword(s):  
Interleukin 6 ◽  
Terminal Differentiation ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Normal Numbers ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Additional Loss

Multiple hematopoietic cytokines can stimulate granulopoiesis; however, their relative importance in vivo and mechanisms of action remain unclear. We recently reported that granulocyte colony-stimulating factor receptor (G-CSFR)-deficient mice have a severe quantitative defect in granulopoiesis despite which phenotypically normal neutrophils were still detected. These results confirmed a role for the G-CSFR as a major regulator of granulopoiesis in vivo, but also indicated that G-CSFR independent mechanisms of granulopoiesis must exist. To explore the role of interleukin-6 (IL-6) in granulopoiesis, we generated IL-6 × G-CSFR doubly deficient mice. The additional loss of IL-6 significantly worsened the neutropenia present in young adult G-CSFR–deficient mice; moreover, exogenous IL-6 stimulated granulopoiesis in vivo in the absence of G-CSFR signals. Near normal numbers of myeloid progenitors were detected in the bone marrow of IL-6 × G-CSFR–deficient mice and their ability to terminally differentiate into mature neutrophils was observed. These results indicate that IL-6 is an independent regulator of granulopoiesis in vivo and show that neither G-CSFR or IL-6 signals are required for the commitment of multipotential progenitors to the myeloid lineage or for their terminal differentiation.

scholarly journals In vitro and in vivo effects of recombinant human granulocyte colony-stimulating factor on neutrophil functions.

1989 ◽  
Vol 35 (6) ◽  
pp. 647-652
Author(s):  
Akimichi Ohsaka ◽  
Seiichi Kitagawa ◽  
Akira Yuo ◽  
Takashi Obata ◽  
Youichi Amemiya ◽  
...  
Keyword(s):  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
In Vivo Effects ◽  
Stimulating Factor

scholarly journals Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus

2013 ◽  
Vol 82 (3) ◽  
pp. 1315-1325 ◽  
Author(s):  
Lauren M. Lilly ◽  
Michaella Scopel ◽  
Michael P. Nelson ◽  
Ashley R. Burg ◽  
Chad W. Dunaway ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Cell Contact ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Content Type ◽  
Eosinophil Peroxidase ◽  
Stimulating Factor ◽  
Deficient Mice

ABSTRACTExposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.

Ligand-induced phosphorylation of the colony-stimulating factor 1 receptor can occur through an intermolecular reaction that triggers receptor down modulation

1990 ◽  
Vol 10 (4) ◽  
pp. 1664-1671
Author(s):  
M Ohtsuka ◽  
M F Roussel ◽  
C J Sherr ◽  
J R Downing
Keyword(s):  
Colony Stimulating Factor ◽  
Intact Cells ◽  
Atp Binding Site ◽  
Truncation Mutant ◽  
Intermolecular Mechanism ◽  
Carboxy Terminal ◽  
Lysine Substitution ◽  
Stimulating Factor

Ligand-induced tyrosine phosphorylation of the human colony-stimulating factor 1 receptor (CSF-1R) could involve either an intra- or intermolecular mechanism. We therefore examined the ability of a CSF-1R carboxy-terminal truncation mutant to phosphorylate a kinase-defective receptor, CSF-1R[met 616], that contains a methionine-for-lysine substitution at its ATP-binding site. By using an antipeptide serum that specifically reacts with epitopes deleted from the enzymatically competent truncation mutant, cross-phosphorylation of CSF-1R[met 616] on tyrosine was demonstrated, both in immune-complex kinase reactions and in intact cells stimulated with CSF-1. Both in vitro and in vivo, CSF-1R[met 616] was phosphorylated on tryptic peptides identical to those derived from wild-type CSF-1R, suggesting that receptor phosphorylation on tyrosine can proceed via an intermolecular interaction between receptor monomers. When expressed alone, CSF-1R[met 616] did not undergo ligand-induced down modulation, but its phosphorylation in cells coexpressing the kinase-active truncation mutant accelerated its degradation.

scholarly journals Neutrophils express the high affinity receptor for IgG (Fc gamma RI, CD64) after in vivo application of recombinant human granulocyte colony- stimulating factor

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 885-889 ◽  
Author(s):  
R Repp ◽  
T Valerius ◽  
A Sendler ◽  
M Gramatzki ◽  
H Iro ◽  
...  
Keyword(s):  
Fc Receptors ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
High Affinity ◽  
Healthy Donors ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Stimulating Factor

Abstract Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]), connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16), but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore, expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL, the median MFI of neutrophils from G-CSF patients (median, 4.78; range, 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001, respectively) than the median MFI of patients not receiving G-CSF (median, 1.23; range, 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median, 1.04; range, 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G- CSF injections, but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity, but only minor increments in Fc gamma RI expression were observed. Thus, during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI, CD64).

scholarly journals The influence in vivo of murine colony-stimulating factor-1 on myeloid progenitor cells in mice recovering from sublethal dosages of cyclophosphamide

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 913-918 ◽  
Author(s):  
HE Broxmeyer ◽  
DE Williams ◽  
S Cooper ◽  
A Waheed ◽  
RK Shadduck
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Colony Stimulating Factor ◽  
Myeloid Progenitor ◽  
Accessory Cells ◽  
Myeloid Progenitor Cells ◽  
In Vivo Administration ◽  
Stimulating Factor

Abstract Pure murine colony-stimulating factor-1 (CSF-1) was assessed for its effects in vivo in mice pretreated seven days earlier with a sublethal dosage of cyclophosphamide. The multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in these mice were in a slowly cycling or noncycling state. Intravenous administration of 20,000 units of CSF-1 to these mice stimulated the hematopoietic progenitors into a rapidly cycling state in the marrow and spleen within three hours. Significant increases in absolute numbers of marrow and spleen CFU-GM and spleen BFU-E and CFU-GEMM were also detected. No endotoxin was detected in the CSF-1 preparation by Limulus lysate assay, and treatment of CSF-1 at 100 degrees C for 20 to 30 minutes completely inactivated the in vitro and in vivo stimulating effects. The effects of CSF-1 were not mimicked by the in vivo administration of 0.1 to 10 ng Escherichia coli lipopolysaccharide. These results suggest that the effects of CSF-1 in vivo were not due to contaminating endotoxin or to a nonspecific protein effect. CSF-1 did not enhance colony formation by BFU-E or stimulate colony formation by CFU-GEMM in vitro, thus suggesting that at least some of the effects of CSF-1 noted in vivo are probably indirect and mediated by accessory cells.

scholarly journals The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo

Blood ◽  
1994 ◽  
Vol 84 (5) ◽  
pp. 1543-1552 ◽  
Author(s):  
VF Quesniaux ◽  
S Wehrli ◽  
C Steiner ◽  
J Joergensen ◽  
HJ Schuurman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
T Cell ◽  
T Cell Response ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Hematopoietic Recovery ◽  
Stimulating Factor

Abstract The immunosuppressive drug rapamycin suppresses T-cell activation by impairing the T-cell response to lymphokines such as interleukin-2 (IL- 2) and interleukin-4 (IL-4). In addition, rapamycin blocks the proliferative response of cell lines to a variety of hematopoietic growth factors, including interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage- colony stimulating factor (GM-CSF), and kit ligand (KL), suggesting that it should be a strong inhibitor of hematopoiesis. In this report, we studied the effects of rapamycin on different hematopoietic cell populations in vitro and in vivo. In vitro, rapamycin inhibited the proliferation of primary bone marrow cells induced by IL-3, GM-CSF, KL, or a complex mixture of factors present in cell-conditioned media. Rapamycin also inhibited the multiplication of colony-forming cells in suspension cultures containing IL-3 plus interleukin-1 (IL-1) or interleukin-11 (IL-11) plus KL. In vivo, treatment for 10 to 28 days with high doses of rapamycin (50 mg/kg/d, orally) had no effect on myelopoiesis in normal mice, as measured by bone marrow cellularity, proliferative capacity, and number of colony-forming progenitors. In contrast, the same treatment strongly suppressed the hematopoietic recovery normally seen 10 days after an injection of 5-fluorouracil (5- FU; 150 mg/kg, intravenously [i.v.]). Thus, rapamycin may be detrimental in myelocompromised individuals. In addition, the results suggest that the rapamycin-sensitive cytokine-driven pathways are essential for hematopoietic recovery after myelodepression, but not for steady-state hematopoiesis.

Sign in / Sign up

Export Citation Format

Share Document