Systematic cytokine receptor profiling reveals GM-CSF as a novel TLR-independent activator of human plasmacytoid predendritic cells

Blood ◽  
2010 ◽  
Vol 115 (24) ◽  
pp. 5037-5040 ◽  
Author(s):  
Cristina Ghirelli ◽  
Raphaël Zollinger ◽  
Vassili Soumelis
Keyword(s):  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Toll Like Receptor ◽  
Microbial Infection ◽  
Systematic Analysis ◽  
Gm Csf ◽  
Protein Levels ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Activation Pathways

Abstract Human plasmacytoid predendritic cells (pDCs) can be activated during microbial infection through Toll-like receptor engagement. They are also involved in nonmicrobial inflammatory diseases, but their activation pathways in this context remain elusive. To identify Toll-like receptor-independent pDC activators, we performed a systematic analysis of cytokine receptors on primary human pDCs. Six receptors were expressed both at mRNA and protein levels: interleukin-3 receptor (IL-3R), IL-6R, IL-10R, IL-18R, interferon-γ receptor, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Only GM-CSF and IL-3 were able to efficiently promote pDC survival and induce their differentiation into dendritic cells. Allogeneic naive CD4 T cells primed with GM-CSF–activated pDCs produced more interferon-γ and less IL-4 and IL-10 compared with IL-3–activated pDCs, indicating a shift in the Th1/Th2 balance. Our data point at a novel function of GM-CSF, which may serve as a link between a pathologic inflammatory environment, pDC activation, and the modulation of CD4 T-cell responses.

Role for Bcl-xL in Delayed Eosinophil Apoptosis Mediated by Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-5

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 778-783 ◽  
Author(s):  
Birgit Dibbert ◽  
Isabelle Daigle ◽  
Doris Braun ◽  
Corinna Schranz ◽  
Martina Weber ◽  
...  
Keyword(s):  
Inflammatory Cells ◽  
Colony Stimulating Factor ◽  
Interleukin 5 ◽  
Gm Csf ◽  
Protein Levels ◽  
Tissue Eosinophilia ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Eosinophil Apoptosis

Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils. © 1998 by The American Society of Hematology.

Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1423-1431 ◽  
Author(s):  
Stephan von Gunten ◽  
Shida Yousefi ◽  
Michael Seitz ◽  
Stephan M. Jakob ◽  
Thomas Schaffner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Interferon Α ◽  
Gm Csf ◽  
Independent Form ◽  
Blood Neutrophils ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Induced Apoptosis

Abstract We report about new apoptotic and non-apoptotic death pathways in neutrophils that are initiated via the surface molecule sialic acid-binding immunoglobulin-like lectin (Siglec)-9. In normal neutrophils, Siglec-9 ligation induced apoptosis. Inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated increased Siglec-9, but normal Fas receptor-mediated cytotoxic responses when compared with normal blood neutrophils. The increased Siglec-9-mediated death was mimicked in vitro by short-term preincubation of normal neutrophils with proinflammatory cytokines, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-α (IFN-α), and IFN-γ, and was demonstrated to be caspase independent. Experiments using scavengers of reactive oxygen species (ROS) or neutrophils unable to generate ROS indicated that both Siglec-9-mediated caspase-dependent and caspase-independent forms of neutrophil death depend on ROS. Interestingly, the caspase-independent form of neutrophil death was characterized by cytoplasmic vacuolization and several other nonapoptotic morphologic features, which were also seen in neutrophils present in joint fluids from rheumatoid arthritis patients. Taken together, these data suggest that apoptotic (ROS- and caspase-dependent) and nonapoptotic (ROS-dependent) death pathways are initiated in neutrophils via Siglec-9. The new insights have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases such as sepsis and rheumatoid arthritis. (Blood. 2005;106:1423-1431)

Interferon-γ switches monocyte differentiation from dendritic cells to macrophages

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Yves Delneste ◽  
Peggy Charbonnier ◽  
Nathalie Herbault ◽  
Giovanni Magistrelli ◽  
Gersende Caron ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Interferon Γ ◽  
Transcriptional Level ◽  
Colony Stimulating Factor ◽  
Monocyte Differentiation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Human monocytes differentiate into dendritic cells (DCs) or macrophages according to the nature of environmental signals. Monocytes stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) yield DCs. We tested here whether interferon-γ (IFN-γ), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-γ to IL-4 plus GM-CSF–stimulated monocytes switches their differentiation from DCs to CD14−CD64+ macrophages. IFN-γ increases macrophage colony-stimulating factor (M-CSF) and IL-6 production by IL-4 plus GM-CSF–stimulated monocytes by acting at the transcriptional level and acts together with IL-4 to up-regulate M-CSF but not IL-6 production. IFN-γ also increases M-CSF receptor internalization. Results from neutralizing experiments show that both M-CSF and IL-6 are involved in the ability of IFN-γ to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-γ is limited to early stages of differentiation. When added to immature DCs, IFN-γ up-regulates IL-6 but not M-CSF production and does not convert them to macrophages, even in the presence of exogenous M-CSF. In conclusion, IFN-γ shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-γ controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-γ orchestrates the outcome of specific immune responses.

scholarly journals CXC chemokine receptor 3 expression on CD34+hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon γ–inducible protein 10 and monokine induced by interferon γ

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1230-1238 ◽  
Author(s):  
Tan Jinquan ◽  
Sha Quan ◽  
Henrik H. Jacobi ◽  
Chen Jing ◽  
Anders Millner ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitors ◽  
Human Cord Blood ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Inducible Protein ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract CXC chemokine receptor 3 (CXCR3), which is known to be expressed predominately on memory and activated T lymphocytes, is a receptor for both interferon γ (IFN-γ)–inducible protein 10 (γIP-10) and monokine induced by IFN-γ (Mig). We report the novel finding that CXCR3 is also expressed on CD34+ hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34+ progenitors. Freshly isolated CD34+progenitors expressed low levels of CXCR3 messenger RNA, but this expression was highly up-regulated by GM-CSF, as indicated by a real-time quantitative reverse transcriptase–polymerase chain reaction technique. γIP-10 and Mig induced chemotaxis of GM-CSF–stimulated CD34+ progenitors by means of CXCR3, since an anti-CXCR3 monoclonal antibody (mAb) was found to block γIP-10–induced and Mig-induced CD34+ progenitor chemotaxis. These chemotactic attracted CD34+ progenitors are colony-forming units—granulocyte-macrophage. γIP-10 and Mig also induced GM-CSF–stimulated CD34+ progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 mAb blocked these functions of γIP-10 and Mig but not of chemokine stromal cell–derived factor 1α. γIP-10–induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF–stimulated CD34+progenitors. Moreover, γIP-10 and Mig stimulated CXCR3 redistribution and cellular polarization in GM-CSF–stimulated CD34+progenitors. These results indicate that CXCR3–γIP-10 and CXCR3–Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment for the physiologic and pathophysiologic events of differentiation of CD34+ hematopoietic progenitors into lymphoid and myeloid stem cells, subsequently immune and inflammatory cells. These processes include transmigration, relocation, differentiation, and maturation of CD34+ hematopoietic progenitors.

Immunologic and functional evidence for anti–Siglec-9 autoantibodies in intravenous immunoglobulin preparations

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4255-4259 ◽  
Author(s):  
Stephan von Gunten ◽  
Alexander Schaub ◽  
Monique Vogel ◽  
Beda M. Stadler ◽  
Sylvia Miescher ◽  
...  
Keyword(s):  
Cell Death ◽  
Intravenous Immunoglobulin ◽  
Ivig Therapy ◽  
Interferon Γ ◽  
Gm Csf ◽  
Immunoglobulin Preparations ◽  
Additional Cell ◽  
Dependent Cell ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract Human intravenous immunoglobulin (IVIg) preparations are increasingly used for the treatment of autoimmune diseases. Earlier work demonstrated the presence of autoantibodies against Fas in IVIg, suggesting that IVIg might be able to induce caspase-dependent cell death in Fas-sensitive cells. In this study, we demonstrate that sialic acid–binding Ig-like lectin 9 (Siglec) represents a surface molecule on neutrophils that is activated by IVIg, resulting in caspase-dependent and caspase-independent forms of cell death. Neutrophil death was mediated by naturally occurring anti–Siglec-9 autoantibodies present in IVIg. Moreover, the efficacy of IVIg-mediated neutrophil killing was enhanced by the proinflammatory cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN–γ), and this additional cell death required reactive oxygen species (ROSs) but not caspases. Anti– Siglec-9 autoantibody–depleted IVIg failed to induce this caspase-independent neutrophil death. These findings contribute to our understanding of how IVIg preparations exert their immunoregulatory effects under pathologic conditions and may provide a possible explanation for the neutropenia that is sometimes seen in association with IVIg therapy.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 630-637 ◽  
Author(s):  
Stefan Faderl ◽  
David Harris ◽  
Quin Van ◽  
Hagop M. Kantarjian ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Protein Levels ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

AbstractHigh levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF–responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5′-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)–Stat inhibitor AG490 abrogated GM-CSF–induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat–dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.

scholarly journals Dexamethasone Attenuates Oncostatin M Production via Suppressing of PI3K/Akt/NF-κB Signaling in Neutrophil-like Differentiated HL-60 Cells

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 129
Author(s):  
Na-Ra Han ◽  
Seong-Gyu Ko ◽  
Hi-Joon Park ◽  
Phil-Dong Moon
Keyword(s):  
Inflammatory Diseases ◽  
Oncostatin M ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phosphatidylinositol 3 Kinase ◽  
Inflammatory Reactions ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Polymerase Chain ◽  
Macrophage Colony ◽  
Signal Cascades

Oncostatin M (OSM) plays a role in various inflammatory reactions, and neutrophils are the main source of OSM in pulmonary diseases. However, there is no evidence showing the mechanism of OSM production in neutrophils. While dexamethasone (Dex) has been known to exert anti-inflammatory activity in various fields, the precise mechanisms of OSM downregulation by Dex in neutrophils remain to be determined. Here, we examined how OSM is produced in neutrophil-like differentiated HL-60 cells. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis were utilized to assess the potential of Dex. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation resulted in OSM elevation in neutrophil-like dHL-60 cells. OSM elevation induced by GM-CSF is regulated by phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor (NF)-kB signal cascades. GM-CSF stimulation upregulated phosphorylated levels of PI3K or Akt or NF-κB in neutrophil-like dHL-60 cells. Treatment with Dex decreased OSM levels as well as the phosphorylated levels of PI3K or Akt or NF-κB in neutrophil-like dHL-60 cells. Our findings show the potential of Dex in the treatment of inflammatory diseases via blocking of OSM.

scholarly journals Bone marrow and splenic granulocyte-macrophage colony-stimulating factor and transforming growth factor-beta mRNA levels in irradiated mice

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2130-2136 ◽  
Author(s):  
CM Chang ◽  
A Limanni ◽  
WH Baker ◽  
ME Dobson ◽  
JF Kalinich ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mrna Levels ◽  
Tgf Beta ◽  
Gm Csf ◽  
Protein Levels ◽  
Macrophage Colony Stimulating Factor ◽  
Growth Factor Beta ◽  
Macrophage Colony ◽  
Stimulating Factor

The effects of a myeloablative sublethal 775 cGy 60C gamma radiation exposure on endogenous bone marrow (BM) and splenic granulocyte- macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta (TGF-beta) mRNA levels were assayed in B6D2F1 female mice. BM and spleen were harvested from normal mice and irradiated mice on days 2, 4, 7, 10, and 14 after exposure. Cytokine mRNA levels were determined using reverse transcription-polymerase chain reaction. After irradiation, GM-CSF mRNA levels were significantly increased in the BM from days 2 to 10 and in the spleen from days 4 to 10. However, when BM and splenic GM-CSF protein levels were measured using Western dot blot, no increased protein levels were detected. Serum GM-CSF levels were likewise unchanged. Radiation exposure did not affect BM or splenic TGF- beta mRNA levels and this cytokine is known to be produced by cell populations similar to those that produce GM-CSF. These data suggest that radiation injury to hemopoietic tissues results in differential effects on GM-CSF and TGF-beta mRNA levels and that, in the case of GM- CSF, increased mRNA levels are not matched by increased protein production.

scholarly journals Hematopoietic Effects of Paeoniflorin and Albiflorin on Radiotherapy-Induced Myelosuppression Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yingli Zhu ◽  
Linyuan Wang ◽  
Zhihui Yang ◽  
Jingxia Wang ◽  
Wei Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
White Blood Cells ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Protein Levels ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Paeonia lactifloraroot (baishao in Chinese) is a commonly used herb in traditional Chinese medicine (TCM). Paeoniflorin (PF) and albiflorin (AF) are two major active constituents ofP. lactiflora. In this paper, we aimed to investigate the hematopoietic effects of PF and AF on myelosuppression mice induced by radiotherapy and to explore the underlying mechanism. The finding indicated that PF and AF significantly increased the numbers of white blood cells (WBC) and reversed the atrophy of thymus. Furthermore, PF and AF increased the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) and reduced the levels of tumor necrosis factor-α(TNF-α) in serum and increased the level of colony-stimulating factor (G-CSF) in plasma. Lastly, PF and AF not only enhanced the mRNA levels of GM-CSF and G-CSF in the spleens, but also increased the protein levels of G-CSF and GM-CSF in bone marrow. Our results suggest that PF and AF may promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model.

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