scholarly journals Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer

2003 ◽  
Vol 197 (9) ◽  
pp. 1213-1219 ◽  
Author(s):  
Thomas Enzler ◽  
Silke Gillessen ◽  
John P. Manis ◽  
David Ferguson ◽  
James Fleming ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Tumor Development ◽  
Interferon Γ ◽  
Systemic Lupus Erythematosis ◽  
Critical Determinant ◽  
Gm Csf ◽  
Infection And Inflammation ◽  
Macrophage Colony ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.

Granulocyte-Macrophage Colony-Stimulating Factor Rescues TF-1 Leukemia Cells From Ionizing Radiation-Induced Apoptosis Through a Pathway Mediated by Protein Kinase Cα

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 416-424 ◽  
Author(s):  
Mary L. Kelly ◽  
Yan Tang ◽  
Nitsa Rosensweig ◽  
Sanda Clejan ◽  
Barbara S. Beckman
Keyword(s):  
Protein Kinase ◽  
Ionizing Radiation ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Pkc Isoforms ◽  
Radiation Induced ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Induced Apoptosis ◽  
Stimulating Factor

Abstract Protein kinase C (PKC) activity has a recognized role in mediating apoptosis. However, the role of individual PKC isoforms in apoptosis is poorly defined. Therefore, we investigated the translocation of individual PKC isoforms during radiation-induced apoptosis with and without rescue from apoptosis by granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human erythroleukemia cell line TF-1. PKCα was translocated from the particulate to cytosolic fraction of TF-1 cells within 5 minutes of treatment with apoptosis-inducing levels of ionizing radiation. However, this postirradiation translocation did not occur when cells were rescued from apoptosis by GM-CSF. Furthermore, treatment of cells with Gö6976, an inhibitor of classical PKC isoforms, abrogated the rescue effect of GM-CSF. The calcium-independent novel PKC isoform, PKCδ appeared to be degraded in both the particulate and cytosolic fractions of TF-1 cells after treatment with apoptosis-inducing levels of ionizing radiation in either the presence or absence of GM-CSF rescue. Levels of ceramide, a lipid mediator of apoptosis, were measured at 2, 4, 8, 10, and 60 minutes after treatment with ionizing radiation and were substantially reduced in TF-1 cells rescued from apoptosis by GM-CSF compared with apoptotic TF-1 cells. The largest decrease in ceramide production seen was at 4 minutes postirradiation, with a 46% reduction in ceramide levels in TF-1 cells rescued from apoptosis by GM-CSF compared with those in apoptotic TF-1 cells. Because ceramide has been shown to affect PKCα subcellular distribution, these data implicate a role for ceramide in mediating the rapid postirradiation translocation and inhibition of PKCα in TF-1 cells not rescued from apoptosis by GM-CSF. Expression of the antiapoptotic protein Bcl-2 doubled in TF-1 cells rescued from apoptosis by GM-CSF, but did not increase in unrescued cells. Our findings suggest that activated PKCα and increased expression of Bcl-2 after γ irradiation determine survival in TF-1 cells rescued from apoptosis with GM-CSF and that PKCδ plays a role in mediating signals involved in sensing cellular damage and/or regulation of cell damage repair.

scholarly journals A Combination of Geniposide and Chlorogenic Acid Combination Ameliorates Nonalcoholic Steatohepatitis in Mice by Inhibiting Kupffer Cell Activation

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xin Xin ◽  
Yue Jin ◽  
Xin Wang ◽  
Beiyu Cai ◽  
Ziming An ◽  
...  
Keyword(s):  
Chlorogenic Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Cell Activation ◽  
Raw264.7 Cells ◽  
Chemical Components ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony ◽  
Underlying Mechanisms ◽  
Factor Α

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide. Activation of Kupffer cells (KCs) is central to the development of diet-induced NASH. We investigated whether a combination of two active chemical components, geniposide and chlorogenic acid (GC), at a specific ratio (67 : 1), ameliorates diet-induced NASH and the underlying mechanisms involved. C57BL/6J mice exposed to a high-fat and high-cholesterol (HFHC) diet containing cholesterol, choline, and high-sugar drinking water, as well as RAW264.7 cells stimulated with lipopolysaccharide (LPS) were studied. The combination exerted a therapeutic effect on HFHC-induced NASH in mice. Simultaneously, GC was found to reduce the expression of cytokines secreted by hepatic macrophages, including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, monocyte chemotactic protein 1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, GC reduced the number of KCs expressing F4/80. Furthermore, TNF-α, inducible nitric oxide synthase (INOS), IL-1β, and IL-6 mRNA and TNF-α protein expression levels were suppressed upon GC treatment in RAW264.7 cells. Our findings suggest that GC has a strong anti-inflammatory effect in NASH, and this effect can be attributed to the suppression of KC activity in the liver.

scholarly journals Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways

2019 ◽  
Vol 13 (1) ◽  
pp. 489-496 ◽  
Author(s):  
Jun Jiang ◽  
Nanyang Zhou ◽  
Pian Ying ◽  
Ting Zhang ◽  
Ruojia Liang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathways ◽  
Tumor Development ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Western Blot Assay ◽  
Anti Oxidant ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Dose Dependent

AbstractEmodin, a major component of rhubarb, has anti-tumor effects in a variety of cancers, influencing multiple steps of tumor development through modulating several signaling pathways. The aim of this study is to examine the effect of emodin on cell apoptosis and explore the underlying mechanisms in human endometrial cancer cells. Here we report that emodin can inhibit KLE cell proliferation and induce apoptosis in a time- and dose-dependent manner. Western blot assay found that emodin was involved in MAPK and PI3K/Akt signaling pathways. Specifically, emodin significantly suppressed the phosphorylation of AKT, and enhanced the phosphorylation of MAPK pathways. Furthermore, the generation of reactive oxygen species (ROS) was up-regulated in KLE cells upon treatment with emodin, while the anti-oxidant agent N-acetyl cysteine (NAC) can inhibit emodin-induced apoptosis and promote the activation of AKT and Bcl-2. Taken together, we revealed that emodin may induce apoptosis in KLE cells through regulating the PI3K/AKT and MAPK signaling pathways, indicating the importance of emodin as an anti-tumor agent.

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 Gas6/TAM Signalling Negatively Regulates Inflammatory Induction of GM-CSF in Mouse Brain Microglia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3281
Author(s):  
Shannon E. Gilchrist ◽  
Grace M. Pennelli ◽  
Sassan Hafizi
Keyword(s):  
Nuclear Translocation ◽  
Cell Types ◽  
Suppressive Effect ◽  
Gene Encoding ◽  
Neuroinflammatory Response ◽  
Gm Csf ◽  
Cellular Source ◽  
Macrophage Colony ◽  
Underlying Mechanisms ◽  
Inflammatory Milieu

Microglia and astrocytes are the main CNS glial cells responsible for the neuroinflammatory response, where they release a plethora of cytokines into the CNS inflammatory milieu. The TAM (Tyro3, Axl, Mer) receptors and their main ligand Gas6 are regulators of this response, however, the underlying mechanisms remain to be determined. We investigated the ability of Gas6 to modulate the CNS glial inflammatory response to lipopolysaccharide (LPS), a strong pro-inflammatory agent, through a qPCR array that explored Toll-like receptor signalling pathway-associated genes in primary cultured mouse microglia. We identified the Csf2 gene, encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), as a major Gas6 target gene whose induction by LPS was markedly blunted by Gas6. Both the Csf2 gene induction and the suppressive effect of Gas6 on this were emulated through measurement of GM-CSF protein release by cells. We found distinct profiles of GM-CSF induction in different glial cell types, with microglia being most responsive during inflammation. Also, Gas6 markedly inhibited the LPS-stimulated nuclear translocation of NF-κB p65 protein in microglia. These results illustrate microglia as a major resident CNS cellular source of GM-CSF as part of the neuroinflammatory response, and that Gas6/TAM signalling inhibits this response through suppression of NF-κB signalling.

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.

Suppression of Interleukin-12 Production by Human Monocytes After Preincubation With Lipopolysaccharide

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1717-1726
Author(s):  
Miriam Wittmann ◽  
Vivi-Ann Larsson ◽  
Petra Schmidt ◽  
Gabriele Begemann ◽  
Alexander Kapp ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Interleukin 12 ◽  
No Production ◽  
Human Monocytes ◽  
Gm Csf ◽  
Experimental Approaches ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Specific Priming

Interleukin-12 (IL-12) is a potent proinflammatory and immunoregulatory cytokine skewing T lymphocytes to express a type 1 cytokine pattern. Optimal expression of IL-12 mRNA and bioactivity in vitro requires specific priming of monocytes by interferon-γ (IFN-γ) or granulocyte-macrophage colony-stimulating factor (GM-CSF) before lipopolysaccharide (LPS) stimulation. We show here for the first time that the production of IL-12 by IFN-γ– or GM-CSF–primed human monocytes can be completely suppressed by preincubation with LPS (fromEscherichia coli Serotype 055:B5) for 6 to 24 hours before the priming procedure. A dose-dependent suppression of IL-12p70 was measured on the levels of intracellular cytokine production and cytokine secretion. mRNA studies on the expression of p40 and p35 showed an LPS-induced downregulation of both subunits. The results of several different experimental approaches suggest that IL-12 downregulation was not due to endogenous IL-10, IL-4, prostaglandin E2 (PGE2), tumor necrosis factor- (TNF-), or nitric oxide (NO) production induced by LPS. Moreover, preincubation of monocytes with LPS did not lead to a downregulation of the CD14 antigen, which is an LPS receptor. LPS preincubation in this experimental setting did not result in a general hyporesponsiveness of the monocytes, as IL-6 production as well as IFN-γ–induced upregulation of CD54 did not decline. Downregulation of IL-12 was not due to changes in mRNA stability. These findings show that the immunoregulatory important cytokine, IL-12, underlies itself a complex regulation.

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.

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