scholarly journals Lac water extract inhibits IFN-γ signaling through JAK2-STAT1-IRF1 axis in human melanoma

RSC Advances ◽  
2018 ◽  
Vol 8 (38) ◽  
pp. 21534-21540
Author(s):  
Luhui Li ◽  
Satoru Yokoyama ◽  
Na Han ◽  
Yoshihiro Hayakawa
Keyword(s):  
Infectious Diseases ◽  
Host Defense ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Water Extract ◽  
Interferon Γ ◽  
Human Melanoma ◽  
Ifn Γ

Interferon-γ (IFN-γ) is a cytokine that plays an important role in the host defense of infectious diseases and in immune surveillance during tumor development.

scholarly journals Inhibition of Methylcholanthrene-induced Carcinogenesis by an Interferon γ Receptor–dependent Foreign Body Reaction

2002 ◽  
Vol 195 (11) ◽  
pp. 1479-1490 ◽  
Author(s):  
Zhihai Qin ◽  
Hye-Jung Kim ◽  
Jens Hemme ◽  
Thomas Blankenstein
Keyword(s):  
Dna Damage ◽  
Foreign Body ◽  
Host Defense ◽  
Tissue Damage ◽  
Defense Mechanisms ◽  
Foreign Body Reaction ◽  
Tumor Development ◽  
Interferon Γ ◽  
Ifn Γ ◽  
Deficient Mice

The foreign body reaction is one of the oldest host defense mechanisms against tissue damage which involves inflammation, scarring, and encapsulation. The chemical carcinogen methylcholanthrene (MCA) induces fibrosarcoma and tissue damage in parallel at the injection site. Tumor development induced by MCA but not due to p53-deficiency is increased in interferon-γ receptor (IFN-γR)–deficient mice. In the absence of IFN-γR, MCA diffusion and DNA damage of surrounding cells is increased. Locally produced IFN-γ induces the formation of a fibrotic capsule. Encapsulated MCA can persist virtually life-long in mice without inducing tumors. Together, the foreign body reaction against MCA prevents malignant transformation, probably by reducing DNA damage. This mechanism is more efficient in the presence of IFN-γR. Our results indicates that inflammation and scarring, both suspected to contribute to malignancy, prevent cancer in certain situations.

Expression of Proteinase Inhibitor-9 in Primary AML Blasts and Its Regulation by Interferon-γ: A Potential Immune Escape Mechanism after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3687-3687
Author(s):  
Sabine Hoves ◽  
Alexandra Kolbeck ◽  
Krishna Mondal ◽  
Reinhard Andreesen ◽  
Andreas Mackensen
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Escape ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Ifn Γ ◽  
Immune Escape Mechanisms

Abstract It is well established, that the curative potential of allogeneic peripheral blood stem cell transplantation (allo PBSCT) is due to immunocompetent donor T cells inducing potent anti-neoplastic effects against host tumor cells. This reaction, which is termed graft-versus-leukemia (GVL) effect, is clinically effective against a number of different hematologic malignancies such as myeloid and lymphoid leukemias. Despite great efforts of allo PBSCT in treatment of CML, the 5-year survival rate of AML patients after allo PBSCT is only about 30% due to relapsing disease. The recurrent disease is inefficiently controlled by the immune system, due most likely to the various immune escape mechanisms described for AML blasts including upregulation of anti-apoptotic molecules. Since cytotoxic T lymphocytes (CTL) and natural killer cells are the cells responsible for eliminating leukemic blasts, the most important effector molecule is Granzyme B (GrB). Misdirected GrB is quenched by its specific physiological inhibitor Protease Inhibitor-9 (PI-9) leading to inactivation of GrB. PI-9 expression by tumour cells can be used to escape immune surveillance and its presence has been shown for different tumors e.g. melanoma, colon carcinoma and lymphoma. Despite other regulators, interferon-γ (IFN-γ) has been shown to upregulate PI-9 expression in hepatocytes. Here, we wanted to investigate the expression of PI-9 in primary AML blasts and its regulation by IFN-γ. Using CD34+ positive magnetic selection, we isolated primary blasts with a purity of >90% from 20 AML patients with different FAB subtypes. For detection of PI-9 expression by Western Blotting, whole cell lysates were made from freshly purified blasts and after 24 h +/− 200 IU/ml IFN-γ. In some patients, PI-9 expression was confirmed by FACS analysis with an anti- PI-9 specific monoclonal antibody. Here we describe for the first time, that PI-9 is constitutively expressed in 16/20 (80%) of AML blasts. Treatment of AML blasts with IFN-γ could upregulate PI-9 expression in a dose-dependent manner (2–2,000 IU/ml) and strong expression of PI-9 was detectable in 6/18 patients within 4–5 h after IFN-γ exposure. Of note, a mild upregulation of PI-9 upon 24 h incubation w/o IFN-γ could be detected in 4/18 (22%) patients. We conclude, that cytokines such as IFN-γ which are secreted during the cytokine storm of acute graft-versus-host disease can contribute to the development of immune escape mechanisms in AML blasts.

Posttranslational Regulation of Myc Function in Response to Phorbol Ester/Interferon-γ–Induced Differentiation of v-Myc–Transformed U-937 Monoblasts

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3900-3912 ◽  
Author(s):  
Fuad Bahram ◽  
Siqin Wu ◽  
Fredrik Öberg ◽  
Bernhard Lüscher ◽  
Lars-Gunnar Larsson
Keyword(s):  
Dna Binding ◽  
Phorbol Ester ◽  
Tumor Development ◽  
Constitutive Expression ◽  
Interferon Γ ◽  
Binding Activity ◽  
Response To Treatment ◽  
Induced Differentiation ◽  
Dna Binding Activity ◽  
Ifn Γ

The transcription factors of the Myc/Max/Mad network are important regulators of cell growth, differentiation, and apoptosis and are frequently involved in tumor development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon-γ (IFN-γ) and TPA restores terminal differentiation and G1cell-cycle arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN-γ counteract v-Myc activity has not been unravelled. Our results show that TPA + IFN-γ treatment led to an inhibition of v-Myc– and c-Myc–dependent transcription, and a specific reduction of v-Myc:Max complexes and associated DNA-binding activity, whereas the steady state level of the v-Myc protein was only marginally affected. In contrast, TPA + IFN-γ costimulation neither increased the expression of Mad1 or other mad/mnt family genes nor altered heterodimerization or DNA-binding activity of Mad1. The reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes lead to their dissociation, thus mimicking the effect of TPA + IFN-γ. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an alternative biologically important level of control with potential therapeutic relevance for hematopoietic and other tumors with deregulated Myc expression.

Melanocytes are more responsive to IFN-γ and produce higher amounts of kynurenine than melanoma cells

2016 ◽  
Vol 397 (1) ◽  
pp. 85-90 ◽  
Author(s):  
Renan Orsati Clara ◽  
Nadine Assmann ◽  
Ana Carolina Ramos Moreno ◽  
Janine Baptista Coimbra ◽  
Nadine Nurenberger ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Poor Prognosis ◽  
Interferon Γ ◽  
Melanoma Cells ◽  
Kynurenine Pathway ◽  
Human Melanoma ◽  
Skin Cells ◽  
Metabolic Route ◽  
Skin Physiology ◽  
Ifn Γ

Abstract A key link between amino acid catabolism and immune regulation in cancer is the augmented tryptophan (Trp) catabolism through the kynurenine pathway (KP), a metabolic route induced by interferon-γ (IFN-γ) and related to poor prognosis in melanomas. Besides its role in cancer, IFN-γ plays a key role in the control of pigmentation homeostasis. Here we measured KP metabolites in human melanoma lines and skin melanocytes and fibroblasts in response to IFN-γ. In general, IFN-γ affected KP in skin cells more than in melanoma cells, supporting IFN-γ roles in skin physiology and that of stromal cells in modulating the tumor microenvironment.

scholarly journals Interferon-γ Regulates the Death of M. tuberculosis-Infected Macrophages

2010 ◽  
Vol 3 ◽  
pp. JCD.S2822 ◽  
Author(s):  
Jinhee Lee ◽  
Hardy Kornfeld
Keyword(s):  
Adaptive Immunity ◽  
Host Defense ◽  
Dna Cleavage ◽  
Interferon Γ ◽  
Macrophage Cell ◽  
Independent Manner ◽  
Ifn Γ ◽  
Bacterial Replication ◽  
Dying Cells ◽  
Apoptosis And Necrosis

We previously described a caspase-independent death induced in macrophages by a high intracellular burden of Mycobacterium tuberculosis (Mtb). This death, with features of apoptosis and necrosis, releases viable bacilli for spreading infection. Interferon (IFN)-γ promotes survival of macrophages with a low intracellular Mtb load by inhibiting bacterial replication. Macrophages in naïve hosts are unable to restrict Mtb replication following aerosol transmission, but IFN-γ is increasingly present when adaptive immunity is expressed in the lungs ~2 weeks post-infection. We therefore investigated the effects of IFN-γ on macrophages challenged with Mtb at high multiplicity of infection (MOI). In contrast to the response at low MOI, IFN-γ accelerated the death of heavily infected macrophages and altered the characteristics of the dying cells. IFN-γ increased caspase-dependent DNA cleavage and apoptotic vesicle formation, but it also increased mitochondrial injury and release of LDH and HMGB1 in a caspase-independent manner. Adaptive immunity in tuberculosis (TB), mediated primarily by IFN-γ, has differential effects on Mtb-induced macrophage cell death depending on the intracellular bacillary load. While IFN-γ generally promotes host defense, our data suggest that its effects on heavily infected macrophages could also accelerate necrosis and spreading infection in TB disease.

scholarly journals Suppression of Lymphoma and Epithelial Malignancies Effected by Interferon γ

2002 ◽  
Vol 196 (1) ◽  
pp. 129-134 ◽  
Author(s):  
Shayna E.A. Street ◽  
Joseph A. Trapani ◽  
Duncan MacGregor ◽  
Mark J. Smyth
Keyword(s):  
Tumor Necrosis ◽  
Late Onset ◽  
Tumor Development ◽  
Interferon Γ ◽  
Spontaneous Tumor ◽  
Significant Incidence ◽  
Immunoregulatory Cytokines ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Necrosis Factor

The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-γ and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). Both IFN-γ and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-γ was strain specific. Lymphomas arising in IFN-γ-deficient mice were very nonimmunogenic compared with those derived from pfp-deficient mice, suggesting a comparatively weaker immunoselection pressure by IFN-γ. Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. A significant incidence of late onset adenocarcinoma observed in both IFN-γ– and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance.

scholarly journals Critical Role for Tumor Necrosis Factor–related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development

2002 ◽  
Vol 195 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Mark J. Smyth ◽  
Erika Cretney ◽  
Yoshihiro Hayakawa ◽  
Nobuhiko Kayagaki ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Critical Role ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Neutralizing Monoclonal Antibody ◽  
Ifn Γ ◽  
Necrosis Factor

Natural killer (NK) cells and interferon (IFN)-γ have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell–mediated and IFN-γ–dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-γ. In the absence of TRAIL, NK cells, or IFN-γ, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53+/− mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.

scholarly journals A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma

2021 ◽  
Author(s):  
Anneloes van Duijn ◽  
Karin J. Willemsen ◽  
Nathalie O. P. van Uden ◽  
Lieke Hoyng ◽  
Sterre Erades ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Human Melanoma ◽  
The Cancer Genome Atlas ◽  
Minor Role ◽  
Sequencing Data ◽  
Secondary Role ◽  
A Minor ◽  
Stat Pathway

AbstractCancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.

Antiviral activity of interferon-γ involved in impaired immune function in infectious diseases

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 149-164 ◽  
Author(s):  
Robert Sucher ◽  
Katharina Kurz ◽  
Raimund Margreiter ◽  
Dietmar Fuchs ◽  
Gerald Brandacher
Keyword(s):  
Amino Acid ◽  
Protein Biosynthesis ◽  
Neuropsychiatric Symptoms ◽  
Tumor Development ◽  
Allergic Inflammation ◽  
Interferon Γ ◽  
Chronic Infections ◽  
Activated T Cells ◽  
Erythroid Progenitor ◽  
Ifn Γ

AbstractPro-inflammatory cytokines like interferon-γ (IFN-γ) play dominant roles in pathophysiologic conditions like infections, cardiovascular and neurodegenerative disorders and autoimmune syndromes. As part of its antimicrobial and immunomodulatory armature, the tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase (IDO) is mainly up-regulated in dendritic cells (DCs) and phagocytes by pro-inflammatory stimuli, most notably IFN-γ. By the breakdown of the essential amino acid l-tryptophan along the kynurenine pathway, IDO plays a key role in the inhibition of cell proliferation including that of activated T cells, thereby supporting immune tolerance in mammalian pregnancy, tumor development, allergic inflammation and allotransplantation. IFN-γ-induced tryptophan deprivation also seems to be involved in the pathogenesis of anemia and cachexia when erythroid progenitor cells suffer from insufficient amino acid supply or when protein biosynthesis of the organism is restricted by diminished tryptophan availability. This biochemical cascade seems also to be involved in the production of potentially neurotoxic tryptophan catabolites such as quinolinic acid, which ultimately leads to the development of neuropsychiatric symptoms like cognitive impairment and depression especially in patients suffering from severe and chronic infections.

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