scholarly journals Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b+Peritoneal Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4487-4495 ◽  
Author(s):  
Masato Hoshi ◽  
Yosuke Osawa ◽  
Hiroyasu Ito ◽  
Hirofumi Ohtaki ◽  
Tatsuya Ando ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Cecal Ligation ◽  
Bacterial Count ◽  
Inhibitory Effect ◽  
Chemokine Production ◽  
Bacterial Peritonitis ◽  
Indoleamine 2,3 Dioxygenase ◽  
Peritoneal Cells ◽  
Bone Marrow Derived Cells

ABSTRACTIndoleamine 2,3-dioxygenase-1 (Ido), which catalyzes the first and limiting step of tryptophan catabolism, has been implicated in immune tolerance. However, the roles of Ido in systemic bacterial infection are complicated and remain controversial. To explore this issue, we examined the roles of Ido in bacterial peritonitis and sepsis after cecal ligation and puncture (CLP) in mice by using the Ido inhibitor 1-methyl-d,l-tryptophan (1-MT), by comparing Ido+/+and Ido−/−mice, or by using chimeric mice in which Ido in the bone marrow-derived cells was deficient. Ido expression in the peritoneal CD11b+cells and its metabolitel-kynurenine in the serum were increased after CLP. 1-MT treatment or Ido deficiency, especially in bone marrow-derived cells, reduced mortality after CLP. Compared to Ido+/+mice, Ido−/−mice showed increased recruitment of neutrophils and mononuclear cells into the peritoneal cavity and a decreased bacterial count in the blood accompanied by increased CXCL-2 and CXCL-1 mRNA in the peritoneal cells. Ido has an inhibitory effect on LPS-induced CXCL-2 and CXCL-1 production in cultured peritoneal cells. These findings indicate that inhibition of Ido reduces mortality from peritonitis and sepsis after CLP via recruitment of neutrophils and mononuclear cells by chemokine production in peritoneal CD11b+cells. Thus, blockade of Ido plays a beneficial role in host protection during bacterial peritonitis and sepsis.

scholarly journals Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1408-1411 ◽  
Author(s):  
T Musso ◽  
GL Gusella ◽  
A Brooks ◽  
DL Longo ◽  
L Varesio
Keyword(s):  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Negative Signal

Abstract Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.

scholarly journals Distribution of cells bearing receptors for a colony-stimulating factor (CSF-1) in murine tissues.

1981 ◽  
Vol 91 (3) ◽  
pp. 848-853 ◽  
Author(s):  
P V Byrne ◽  
L J Guilbert ◽  
E R Stanley
Keyword(s):  
Bone Marrow ◽  
Binding Sites ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Mononuclear Phagocytes ◽  
Small Cells ◽  
Phagocytic Cells ◽  
Alveolar Cells ◽  
Peritoneal Cells ◽  
Blood Mononuclear Cells

CSF-1 is a subclass of the colony-stimulating factors that specifically stimulates the growth of mononuclear phagocytes. We used the binding of 125I-CSF-1 at 0 degrees C by single cell suspensions from various murine tissues, in conjunction with radioautography, to determine the frequency of binding cells, their identity, and the number of binding sites per binding cell. For all tissues examined, saturation of binding sites was achieved within 2 h at 2--3 x 10(-10) M 125I-CSF-1. The binding was irreversible and almost completely blocked by a 2 h preincubation with 5 x 10(-10) M CSF-1. 125I-CSF-1 binding was exhibited by 4.3% of bone marrow cells, 7.5% of blood mononuclear cells, 2.4% of spleen cells, 20.5% of peritoneal cells, 11.8% of pulmonary alveolar cells and 0.4% of lymph node cells. Four morphologically distinguishable cell types bound 125I-CSF-1: blast cells; mononuclear cells with a ratio of nuclear to cytoplasmic area (N/C) greater than 1; cells with indented nuclei; and mononuclear cells with N/C less than or equal to 1. No CSF-1 binding cells were detected among blood granulocytes or thymus cells. Bone marrow promyelocytes, myelocytes, neutrophilic granulocytes, eosinophilic granulocytes, nucleated erythroid cells, enucleated erythrocytes, and megakaryocytes also failed to bind. The frequency distribution of grain counts per cell for blood mononuclear cells was homogenous. In contrast, those for bone marrow, spleen, alveolar, and peritoneal cells were heterogeneous. The monocytes in blood or bone marrow (small cells, with either indented nuclei or with N/C greater than 1) were relatively uniformly labeled, possessing approximately 3,000 binding sites per cell. Larger binding cells (e.g., alveolar cells) may possess higher numbers of receptors. It is concluded that CSF-1 binding is restricted to mononuclear phagocytic cells and their precursors and that it can be used to identify both mature and immature cells of this series.

The BAFF Inhibitor AMG523 Blocks Adhesion and Survival of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment: Clinical Implication.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3452-3452 ◽  
Author(s):  
Yu-Tzu Tai ◽  
Jiangchun Xu ◽  
Xian-Feng Li ◽  
Iris Breitkreutz ◽  
Klaus Podar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Bone Marrow Microenvironment ◽  
Minor Role ◽  
Dependent Manner ◽  
Growth And Survival

Abstract We previously identified a role of B-cell activating factor (BAFF), a member of the tumor necrosis factor superfamily, in localization and survival of MM cells in the BM microenvironment (Cancer Res2006, 66:6675–82). In the present study, we examined the potential therapeutic utility of the BAFF inhibitor, AMG523, for treating human MM using MM lines, either sensitive or resistant to conventional chemotherapy, as well as freshly isolated patient MM cells, in the presence or absence of bone marrow stromal cells (BMSCs). AMG523 induces modest cytotoxicity in MM cell lines and patient MM cells, suggesting a minor role of autocrine mechanism of BAFF for MM growth and survival. In the presence of BMSCs, AMG523 significantly decreased growth and survival in dexamethasone (Dex)-sensitive MM1S, Dex-resistant MM1R, INA6 MM cells and in patient MM cells (n=7), in a dose-dependent manner (0.1–10 μg/ml). BAFF-augmented MM adhesion to BMSCs is also blocked by AMG523 at 0.1 mg/ml in MM lines (MM1S, 28PE, INA6), as well as in freshly isolated patient MM cells (n=4). BAFF protects MM cells against dex- and lenalidomide-induced cytotoxicity; conversely, AMG523 blocks BAFF-induced protection against drug-induced apoptosis. Importantly, pretreatment of AMG523 blocks BAFF-induced activation of AKT, nuclear factor kB, and ERK in MM cells, confirming its inhibitory effect on BAFF-mediated adhesion and survival. We next asked whether AMG523 enhances Dex-, bortezomib-, Lenalidomide-induced MM cell cytotoxicity. AMG523 augments the inhibitory effect of Dex and lenalidomide in patient MM cells in the presence of BMSCs. Since osteoclasts (OCLs) secrete BAFF in the bone marrow microenvironment, we further asked whether AMG523 inhibits protection by MM-OCL interaction. OCLs were derived from peripheral blood mononuclear cells from MM patients after 2-week culture with M-CSF and RANKL, and MM cells were added in the presence or absence of AMG523. OCLs significantly increased MM cell survival, evidenced by annexin V and PI staining followed by flow cytometric analysis; conversely, AMG523 blocked MM cell survival by coculture with OCLs. Taken together, our data demonstrate that the novel therapeutic AMG523 blocks the interaction between BAFF and its receptors in human MM, thereby providing the rationale for clinical trials of AMG523 to improve patient outcome in MM.

scholarly journals Toll-Like Receptor 2 Regulates CXC Chemokine Production and Neutrophil Recruitment to the Cornea in Onchocerca volvulus/ Wolbachia-Induced Keratitis

2007 ◽  
Vol 75 (12) ◽  
pp. 5908-5915 ◽  
Author(s):  
Illona Gillette-Ferguson ◽  
Katrin Daehnel ◽  
Amy G. Hise ◽  
Yan Sun ◽  
Eric Carlson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Role ◽  
Corneal Stroma ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Onchocerca Volvulus ◽  
Chemokine Production ◽  
Corneal Haze ◽  
Cxc Chemokine ◽  
Bone Marrow Derived Cells

ABSTRACT The filarial nematode Onchocerca volvulus is the causative organism of river blindness. Our previous studies demonstrated an essential role for endosymbiotic Wolbachia bacteria in corneal disease, which is characterized by neutrophil infiltration into the corneal stroma and the development of corneal haze. To determine the role of Toll-like receptors (TLRs) in neutrophil recruitment and activation, we injected a soluble extract of O. volvulus containing Wolbachia bacteria into the corneal stromata of C57BL/6, TLR2−/−, TLR4−/−, TLR2/4−/−, and TLR9−/− mice. We found an essential role for TLR2, but not TLR4 or TLR9, in neutrophil recruitment to the cornea and development of corneal haze. Furthermore, chimeric mouse bone marrow studies showed that resident bone marrow-derived cells in the cornea can initiate this response. TLR2 expression was also essential for CXC chemokine production by resident cells in the cornea, including corneal fibroblasts, and for neutrophil activation. Taken together, these findings indicate that Wolbachia activates TLR2 on resident bone marrow-derived cells in the corneal stroma to produce CXC chemokines, leading to neutrophil recruitment to the corneal stroma, and that TLR2 mediates O. volvulus/Wolbachia-induced neutrophil activation and development of corneal haze.

The Effect of Rapamycin, 17-AAG and the Combination on the Bone Marrow Microenvironment in Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3476-3476
Author(s):  
Lanie Francis ◽  
Judy Anderson ◽  
Michael Timm ◽  
Noriyoshi Kurihara ◽  
Ujjal Singha ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Inhibitory Effect ◽  
Hsp90 Inhibitor ◽  
Negative Control ◽  
Bone Marrow Microenvironment ◽  
Tubule Formation

Abstract The bone marrow microenvironment in MM is characterized by the presence of upregulated osteoclast activity (OCL) and increased angiogenesis. We have recently demonstrated that the HSP90 inhibitor 17-AAG (provided by the NCI) and the mTOR inhibitor rapamycin (LC Laboratories, MA) have synergistic inhibitory activity on MM cells. The objective of this study was to determine the effect of rapamycin, 17-AAG and the combination on OCL formation and angiogenesis. Rapamycin (0.01–100nM), 17-AAG (10–1000nM) and the combination was tested using an in vitro human OCL formation assay and a human angiogenesis assay (AngioKit, TCS Cellworks, UK). Nonadherent human marrow mononuclear cells (1 x 105/100 μL) were plated in 96-well plates in the presence or absence of DMSO, rapamycin, 17-AAG or the combination. RANKL (100ng/ml) and MCSF (20ng/ml) were added to all wells except control media and MCSF. After 3 weeks, cells were fixed, and the number of OCL-like multinucleated cells were scored. To test the effect of the agents on early OCL precursors, we added the inhibitory agents on days 1, 7 or 14 of the culture. The AngioKit is comprised of human endothelial cells in a 24 well plate. The endothelial cells proliferate and then migrate through the matrix to form tubular structures and anastomosing tubules by 2 weeks. Two control wells were treated with VEGF (+ve control) and two with suramin (−ve control). The optimized medium and test samples were replaced on days 4, 7, and 9 after initial treatment. On day 11, cultures were fixed and stained with antibodies to CD31 to detect vessel formation. The degree of tubule formation was quantitated using computerized image analysis (Angiosys, TCS Cellworks, UK). Single agent rapamycin (20–100nM) inhibited OCL formation by 35% as compared to control in all tested doses indicating that PI3K/mTOR is an important regulator of OCL formation. The effect was similar on day 7 and day 14 indicating that this pathway is important for early and late OCL formation. 17-AAG 100–600nM significantly inhibited OCL formation with 100nM 17-AAG inducing 12% OCL formation as compared to control, while 300 and 600nM completely abrogated OCLs (0% OCLs). This effect was similar at day 7. However, when 17-AAG was added on day 14, it only induced 50–60% reduction in OCL formation indicating that 17-AAG affects early OCL formation. The combination of the two agents completely inhibited OCL formation on day 1 and 7 and led to a 65% reduction in OCLs when added on day 14 of the culture. Rapamycin showed a marked decrease in angiogenesis (similar to the negative control suramin), even at the lowest level tested of 0.01nM. 17-AAG demonstrated some inhibition of angiogenesis at 10 nM, and completely abrogated angiogenesis at 500–1000nM. In summary, rapamycin and 17-AAG inhibit OCL formation and angiogenesis. The effect of 17-AAG was on early OCL formation while rapamycin was on both early and late OCL. These results are contradictory to previous data indicating that 17-AAG increases OCL activity in MM. Rapamycin had a significant inhibitory effect on angiogenesis even at low doses. These results demonstrate that the use of rapamycin analogues and 17-AAG in clinical trials may have a therapeutic effect, not only on MM cells, but also on the bone marrow microenvironment. Supported in part by an ASH Scholar Award and an MMRF grant.

scholarly journals Endothelial cell fitness dictates the source of regenerating liver vasculature

2018 ◽  
Vol 215 (10) ◽  
pp. 2497-2508 ◽  
Author(s):  
Mahak Singhal ◽  
Xiaoting Liu ◽  
Donato Inverso ◽  
Kai Jiang ◽  
Jianing Dai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cell ◽  
Mononuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Cellular Source ◽  
Bone Marrow Derived Cells ◽  
Cell Mobilization ◽  
Marrow Infusion ◽  
Stimulating Factor ◽  
Bone Marrow Infusion

Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone marrow infusion or granulocyte colony–stimulating factor (G-CSF)–mediated progenitor cell mobilization, which resembles clinically relevant stem cell therapy, demonstrated that bone marrow–derived cells did not contribute to the regeneration of liver vasculature after two-thirds partial hepatectomy (PHx). Taken together, the data reconcile many of the discrepancies in the literature and highlight that the cellular source of regenerating endothelium depends on the fitness of the residual vasculature.

Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis

2015 ◽  
Vol 123 (2) ◽  
pp. 409-422 ◽  
Author(s):  
JinChao Hou ◽  
QiXing Chen ◽  
Kai Zhang ◽  
BaoLi Cheng ◽  
GuoHao Xie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Multiorgan Failure ◽  
Cecal Ligation ◽  
Lung Damage ◽  
Peripheral Blood Mononuclear ◽  
Fluorescent Intensity ◽  
Macrophage Phagocytosis ◽  
Sphingosine 1 Phosphate ◽  
Genetic Deletion

Abstract Background: Sepsis is characterized by an inappropriate systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Sphingosine 1-phosphate receptor 2 (S1PR2) modulates endotoxin-induced inflammation in endothelium. However, as a highly expressed S1P receptor in macrophages, its role in regulating macrophage response to bacterial infection remains unclear. Methods: Cecal ligation and puncture or intratracheal instillation of Escherichia coli was induced in wild-type or S1pr2-deficient mice. The antibacterial ability of cell-specific S1PR2 was tested in bone marrow reconstitution mice or mice with macrophage-specific deletion. Signaling molecules responsible for S1PR2-mediated phagocytosis were also measured in the bone marrow–derived macrophages. In addition, S1PR2 expression levels and its correlation with severity of sepsis were determined in critically ill patients (n = 25). Results: Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival (genetic deletion, 0% in S1pr2+/+vs. 78.6% in S1pr2−/−, P < 0.001; pharmaceutical inhibition, 9.1% in vehicle vs. 22.2% in S1PR2 antagonist, P < 0.05). This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages (mean fluorescent intensity, 2035.2 ± 202.1 vs. 407.8 ± 71.6, P < 0.001). Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, whose signaling pathways depend on extracellular stimulators. In septic patients, increased S1PR2 levels in peripheral blood mononuclear cells were positively correlated with the severity of sepsis (r = 0.845, P < 0.001). Conclusions: This study implies that S1PR2, as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as promising therapeutic approaches for sepsis.

scholarly journals Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1408-1411
Author(s):  
T Musso ◽  
GL Gusella ◽  
A Brooks ◽  
DL Longo ◽  
L Varesio
Keyword(s):  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Negative Signal

Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.

scholarly journals Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Paulo Henrique Rosado-de-Castro ◽  
Felipe Gonçalves de Carvalho ◽  
Gabriel Rodriguez de Freitas ◽  
Rosalia Mendez-Otero ◽  
Pedro Moreno Pimentel-Coelho
Keyword(s):  
Bone Marrow ◽  
Intracerebral Hemorrhage ◽  
Clinical Studies ◽  
Hemorrhagic Stroke ◽  
Mononuclear Cells ◽  
Time Window ◽  
Therapeutic Potential ◽  
Cell Therapies ◽  
Life Years ◽  
Bone Marrow Derived Cells

Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

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