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https://www.readbyqxmd.com/read/27913706/stat1-promotes-kras-colon-tumor-growth-and-susceptibility-to-pharmacological-inhibition-of-translation-initiation-factor-eif4a
#1
Shuo Wang, Cedric Darini, Laurent Désaubry, Antonis E Koromilas
The transcription factor STAT1 displays antitumor functions for certain forms of cancer via immunoregulatory and cell-autonomous pathways. Paradoxically, STAT1 can promote the survival of different tumor types treated with chemotherapeutic drugs through mechanisms that are not clearly defined. Herein, we demonstrate that STAT1 displays prosurvival effects in human KRAS colon tumor cells by regulating pathways that converge on the initiation of mRNA translation. Specifically, STAT1 increases PI3K class IB signaling and promotes the downregulation of the programmed cell death protein 4 (PDCD4), a protein with tumor-suppressive properties...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27912061/tumor-interferon-signaling-regulates-a-multigenic-resistance-program-to-immune-checkpoint-blockade
#2
Joseph L Benci, Bihui Xu, Yu Qiu, Tony J Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S M Lee, Kristen E Pauken, Alexander C Huang, Tara C Gangadhar, Ravi K Amaravadi, Lynn M Schuchter, Michael D Feldman, Hemant Ishwaran, Robert H Vonderheide, Amit Maity, E John Wherry, Andy J Minn
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27911817/tnf%C3%AE-stimulated-gene-6-tsg6-activates-macrophage-phenotype-transition-to-prevent-inflammatory-lung-injury
#3
Manish Mittal, Chinnaswamy Tiruppathi, Saroj Nepal, You-Yang Zhao, Dagmara Grzych, Dheeraj Soni, Darwin J Prockop, Asrar B Malik
TNFα-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Here we observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6(-/-) mice compared with WT (TSG6(+/+)) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-κB activation...
November 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27910206/balance-between-il-3-and-type-iinterferons-and-their-interrelationship-with-fasl-dictates-lifespan-and-effector-functions-of-human-basophils
#4
B R Hagmann, A Odermatt, T Kaufmann, C A Dahinden, M Fux
BACKGROUND: In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-α, IFN-β), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation. OBJECTIVE: To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils...
November 5, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27907166/vaccinia-virus-protein-c6-inhibits-type-i-ifn-signalling-in-the-nucleus-and-binds-to-the-transactivation-domain-of-stat2
#5
Jennifer H Stuart, Rebecca P Sumner, Yongxu Lu, Joseph S Snowden, Geoffrey L Smith
The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27905550/deep-sequencing-of-transcriptome-profiling-of-gstm2-knock-down-in-swine-testis-cells
#6
Yuqi Lv, Yi Jin, Yongqiang Zhou, Jianjun Jin, Zhenfa Ma, Zhuqing Ren
Glutathione-S-transferases mu 2 (GSTM2), a kind of important Phase II antioxidant enzyme of eukaryotes, is degraded by nonsense mediated mRNA decay due to a C27T substitution in the fifth exon of pigs. As a reproductive performance-related gene, GSTM2 is involved in embryo implantation, whereas, functional deficiency of GSTM2 induces pre- or post-natal death in piglets potentially. To have some insight into the role of GSTM2 in embryo development, high throughput RNA sequencing is performed using the swine testis cells (ST) with the deletion of GSTM2...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27893714/the-lim-protein-ajuba-promotes-colorectal-cancer-cell-survival-through-suppression-of-jak1-stat1-ifit2-network
#7
H Jia, L Song, Q Cong, J Wang, H Xu, Y Chu, Q Li, Y Zhang, X Zou, C Zhang, Y E Chin, X Zhang, Z Li, K Zhu, B Wang, H Peng, Z Hou
The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27881708/il-35-suppresses-lipopolysaccharide-induced-airway-eosinophilia-in-ebi3-deficient-mice
#8
Kyosuke Kanai, Ah-Mee Park, Hiroki Yoshida, Ikuo Tsunoda, Osamu Yoshie
EBI3 functions as the subunit of immune-regulatory cytokines, such as IL-27 and IL-35, by pairing with p28 and p35, respectively. We treated wild-type and EBI3-deficient mice with intratracheal administration of LPS and obtained bronchoalveolar lavage fluid (BALF) 24 h later. Although neutrophils were the predominant cells in BALF from both groups of mice, eosinophils were highly enriched and there was increased production of eosinophil-attracting chemokines CCL11 and CCL24 in BALF of EBI3-deficient mice. The bronchial epithelial cells and alveolar macrophages were the major producers of CCL11 and CCL24...
November 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27879260/antibiotics-impair-murine-hematopoiesis-by-depleting-intestinal-microbiota
#9
Kamilla S Josefsdottir, Megan T Baldridge, Claudine S Kadmon, Katherine Y King
Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses. Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore the effects of antibiotics on hematopoietic progenitors in detail using a murine model. Antibiotic-treated mice exhibited anemia, thrombocytosis, and leukopenia, with pronounced pan-lymphopenia as demonstrated by flow cytometric analysis of peripheral blood. Bone marrow progenitor analysis revealed depletion of hematopoietic stem cells and multipotent progenitors across all subtypes...
November 22, 2016: Blood
https://www.readbyqxmd.com/read/27877014/prognostic-potential-of-an-immune-score-based-on-the-density-of-cd8-t-cells-cd20-b-cells-and-cd33-p-stat1-double-positive-cells-and-hmgb1-expression-within-cancer-nests-in-stage-iiia-gastric-cancer-patients
#10
Jun Dong, Jiao Li, Shiming Liu, Xingyu Feng, Shi Chen, Zhiwei Zhou, Yingbo Chen, Xiaoshi Zhang
OBJECTIVE: There is heterogeneity in the prognosis of gastric cancers staged according to the tumornodes- metastasis (TNM) system. This study evaluated the prognostic potential of an immune score system to supplement the TNM staging system. METHODS: An immunohistochemical analysis was conducted to assess the density of T cells, B cells, and myeloid-derived suppressor cells (MDSCs) in cancer tissues from 100 stage IIIA gastric cancer patients; the expression of the high-mobility group protein B1 (HMGB1) was also evaluated in cancer cells...
October 2016: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
https://www.readbyqxmd.com/read/27873163/an-update-on-the-use-of-immunomodulators-in-primary-immunodeficiencies
#11
REVIEW
Pandiarajan Vignesh, Amit Rawat, Surjit Singh
The genomic revolution in the past decade fuelled by breathtaking advances in sequencing technologies has defined several new genetic diseases of the immune system. Many of these newly characterized diseases are a result of defects in genes involved in immune regulation. The discovery of these diseases has opened a vista of new therapeutic possibilities. Immunomodulatory agents, a hitherto unexplored therapeutic option in primary immunodeficiency diseases have been tried in a host of these newly described maladies...
November 21, 2016: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/27866837/high-density-lipoproteins-exert-pro-inflammatory-effects-on-macrophages-via-passive-cholesterol-depletion-and-pkc-nf-%C3%AE%C2%BAb-stat1-irf1-signaling
#12
Emiel P C van der Vorst, Kosta Theodorou, Yongzheng Wu, Marten A Hoeksema, Pieter Goossens, Christina A Bursill, Taghi Aliyev, Leonie F A Huitema, Sander W Tas, Ine M J Wolfs, Marijke J E Kuijpers, Marion J Gijbels, Casper G Schalkwijk, Debby P Y Koonen, Shahla Abdollahi-Roodsaz, Kimberly McDaniels, Chih-Chieh Wang, Michael Leitges, Toby Lawrence, Jogchum Plat, Miranda Van Eck, Kerry-Anne Rye, Lhousseine Touqui, Menno P J de Winther, Erik A L Biessen, Marjo M P C Donners
Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels...
November 16, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27865863/curcumin-promotes-the-oncoltyic-capacity-of-vesicular-stomatitis-virus-for-the-treatment-of-prostate-cancers
#13
Dylan J Fehl, Maryam Ahmed
Vesicular stomatitis virus (VSV) matrix (M) protein mutants have been studied as oncolytic agents due to their capacity to effectively kill cancer cells while exhibiting low virulence in vivo. Despite encouraging results, many cancer cells maintain resistance to oncolytic VSV mutants in part due to residual antiviral responses. We sought to determine whether combination of VSV with natural agents with anti-tumor properties, such as curcumin, resveratrol, and flavokavain B, would enhance tumor cell killing in a prostate cancer model...
November 16, 2016: Virus Research
https://www.readbyqxmd.com/read/27865166/ethyl-pyruvate-inhibits-the-acetylation-and-release-of-hmgb1-via-effects-on-sirt1-stat-signaling-in-lps-activated-raw264-7-cells-and-peritoneal-macrophages
#14
Young Min Kim, Eun Jung Park, Jung Hwan Kim, Sang Won Park, Hye Jung Kim, Ki Churl Chang
High mobility group box 1 (HMGB1), a cytokine present in the late phase of sepsis, may be a potential target for the treatment of sepsis. For HMGB1 to be actively secreted from macrophages during infections, it must be post-translationally modified. Although ethyl pyruvate (EP), a simple aliphatic ester derived from pyruvic acid, has been shown to inhibit the release of HMGB1 in lipopolysaccharide (LPS)-treated RAW 264.7 cells, the underlying mechanism(s) are not yet clear. We investigated the hypothesis that the upregulation of SIRT1 by EP might promote the deacetylation of HMGB1, which reduces HMGB1 release in LPS-activated macrophages...
November 16, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27862996/tannic-acid-inhibits-egfr-stat1-3-and-enhances-p38-stat1-signalling-axis-in-breast-cancer-cells
#15
Pramod Darvin, Youn Hee Joung, Dong Young Kang, Nipin Sp, Hyo Joo Byun, Tae Sook Hwang, Hema Sasidharakurup, Chi Ho Lee, Kwang Hyun Cho, Kyung Do Park, Hak Kyo Lee, Young Mok Yang
Tannic acid (TA), a naturally occurring polyphenol, is a potent anti-oxidant with anti-proliferative effects on multiple cancers. However, its ability to modulate gene-specific expression of tumour suppressor genes and oncogenes has not been assessed. This work investigates the mechanism of TA to regulate canonical and non-canonical STAT pathways to impose the gene-specific induction of G1-arrest and apoptosis. Regardless of the p53 status and membrane receptors, TA induced G1-arrest and apoptosis in breast cancer cells...
November 15, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27862183/the-antiviral-cytokine-interferon-gamma-restricts-neural-stem-progenitor-cell-proliferation-through-activation-of-stat1-and-modulation-of-retinoblastoma-protein-phosphorylation
#16
Apurva Kulkarni, Taylor J Scully, Lauren A O'Donnell
Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFNγ), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules...
November 15, 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/27858144/th9-and-other-il-9-producing-cells-in-allergic-asthma
#17
REVIEW
Sonja Koch, Nina Sopel, Susetta Finotto
Allergic asthma is a worldwide increasing chronic disease of the airways which affects more than 300 million people. It is associated with increased IgE, mast cell activation, airway hyperresponsiveness (AHR), mucus overproduction and remodeling of the airways. Previously, this pathological trait has been associated with T helper type 2 (Th2) cells. Recently, different CD4(+) T cell subsets (Th17, Th9) as well as cells of innate immunity, like mast cells and innate lymphoid cells type 2 (ILC2s), which are all capable of producing the rediscovered cytokine IL-9, are known to contribute to this disease...
November 17, 2016: Seminars in Immunopathology
https://www.readbyqxmd.com/read/27856304/a-heterozygous-dominant-negative-mutation-in-the-coiled-coil-domain-of-stat1-is-the-cause-of-autosomal-dominant-mendelian-susceptibility-to-mycobacterial-diseases
#18
Masahiro Ueki, Masafumi Yamada, Kenta Ito, Yusuke Tozawa, Saeko Morino, Yuho Horikoshi, Hidetoshi Takada, Shimaa Said Mohamed Ali Abdrabou, Shunichiro Takezaki, Ichiro Kobayashi, Tadashi Ariga
Heterozygous dominant-negative mutations of STAT1 are responsible for autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD). So far, only 7 mutations have been previously described and are localized to 3 domains: the DNA-binding domain, the SH2 domain, and the tail segment. In this study, we demonstrated the first coiled-coil domain (CCD) mutation of c.749G>C, p.G250A (G250A) in STAT1 as a genetic cause of AD-MSMD in a patient with mycobacterial multiple osteomyelitis. This de novo heterozygous mutation was shown to have a dominant-negative effect on the gamma-activated sequence (GAS) transcriptional activity following IFN-γ stimulation, which could be attributable to the abolished phosphorylation of STAT1 from the wild-type (WT) allele...
November 14, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27855602/targeting-stat1-in-both-cancer-and-insulin-resistance-diseases
#19
Chen Meng, Li-Bin Guo, Xiaolong Liu, Yih-Hsin Chang, Yao Lin
With the rapid development of targeted therapy and our understanding of the underlying molecular mechanisms, drug repurposing is becoming trendy in drug development field. Drugs that display promising therapeutic effects towards multiple diseases tend to target important signaling proteins. Insulin resistance and obesity are strongly associated and both are reported to be correlated with cancer, suggesting they may be linked via some critical pathways. Signal transducers and activator of transcription 1 (STAT1) is an important transcription factor involved in the regulation of multiple cellular processes such as proliferation, survival, inflammation, and angiogenesis...
November 17, 2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/27855377/inhibition-of-stat-pathway-impairs-anti-hepatitis-c-virus-effect-of-interferon-alpha
#20
Lan-Juan Zhao, Sheng-Fei He, Yuan Liu, Ping Zhao, Zhong-Qi Bian, Zhong-Tian Qi
BACKGROUND/AIMS: Signal transducer and activator of transcription (STAT) pathway plays an important role in antiviral efficacy of interferon alpha (IFN-α). IFN-α is the main therapeutic against hepatitis C virus (HCV) infection. We explored effects of IFN-α on HCV replication and antiviral gene expression by targeting STAT. METHODS: In response to IFN-α, STAT status, HCV replication, and antiviral gene expression were analyzed in human hepatoma Huh7.5.1 cells before and after cell culture-derived HCV infection...
2016: Cellular Physiology and Biochemistry
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