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Lucy A Eddowes, Kinda Al-Hourani, Narayan Ramamurthy, Jamie Frankish, Hannah T Baddock, Cynthia Sandor, John D Ryan, Dahlene N Fusco, João Arezes, Eleni Giannoulatou, Sara Boninsegna, Stephane Chevaliez, Benjamin M J Owens, Chia Chi Sun, Paolo Fabris, Maria Teresa Giordani, Diego Martines, Slobodan Vukicevic, John Crowe, Herbert Y Lin, Jan Rehwinkel, Peter J McHugh, Marco Binder, Jodie L Babitt, Raymond T Chung, Matthew W Lawless, Andrew E Armitage, Caleb Webber, Paul Klenerman, Hal Drakesmith
Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity...
December 3, 2018: Nature Microbiology
Benoit Briard, Rajendra Karki, R K Subbarao Malireddi, Anannya Bhattacharya, David E Place, Jayadev Mavuluri, Jennifer L Peters, Peter Vogel, Masahiro Yamamoto, Thirumala-Devi Kanneganti
Invasive pulmonary aspergillosis causes substantial mortality in immunocompromised individuals. Recognition of Aspergillus fumigatus by the host immune system leads to activation of the inflammasome, which provides protection against infection. However, regulation of inflammasome activation at the molecular level is poorly understood. Here, we describe two distinct pathways that coordinately control inflammasome activation during A. fumigatus infection. The C-type lectin receptor pathway activates both MAPK and NF-κB signalling, which leads to induction of downstream mediators, such as the transcription factor IRF1, and also primes the inflammasomes...
December 3, 2018: Nature Microbiology
Na Yu, Min Xue, Weilong Wang, Dongxue Xia, Yajie Li, Xiaofeng Zhou, Dan Pang, Kui Lu, Jinghan Hou, Aijia Zhang, Ting Zhuang, Lidong Wang, Tingmin Chang, Xiumin Li
Oesophageal cancer ranks as one of the most common malignancy in China and worldwide. Although genome-wide association studies and molecular biology studies aim to elucidate the driver molecules in oesophageal cancer progression, the detailed mechanisms remain to be identified. Interestingly, RNF168 (RING finger protein 168) shows a high frequency of gene amplification in oesophageal cancer from TCGA database. Here, we report an important function for RNF168 protein in supporting oesophageal cancer growth and invasion by stabilizing STAT1 protein...
December 3, 2018: Journal of Cellular and Molecular Medicine
Yuzhen Zhou, Qi Wang, Li Chu, Weixing Dai, Xiaozhou Zhang, Jianfeng Chen, Long Zhang, Peipei Ding, Xin Zhang, Hongyu Gu, Pingzhao Zhang, Ling Li, Wei Zhang, Luying Li, Xinyue Lv, Danlei Zhou, Guoxiang Cai, Liang Chen, Kuaile Zhao, Weiguo Hu
OBJECTIVES: We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications. MATERIALS AND METHODS: The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation...
November 28, 2018: Cell Proliferation
Gabriel Rodrigo Fries, Sarwar Khan, Sydney Stamatovich, Elena Dyukova, Consuelo Walss-Bass, Scott D Lane, Joy M Schmitz, Margaret C Wardle
Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD...
2018: PloS One
Ailing Wu, Qingzhe Wu, Yujie Deng, Yuning Liu, Jinqiu Lu, Liansheng Liu, Xiaoling Li, Cheng Liao, Bin Zhao, Hai Song
Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models...
November 5, 2018: EMBO Journal
Che Wang, Honghui Yang, Chuanyu Gao
In this study, we identified candidate biomarkers for heart failure (HF). The gene expression profile GSE57338, containing 117 ischemic cardiomyopathic HF and 136 control samples, was downloaded and analyzed using various bioinformatics approaches. In total, 376 differentially expressed genes (DEGs) were identified, and four modules were explored in protein-protein interaction networks. DEGs (including ankyrin repeat and SOCS box-containing 14 [ASB14]) in the modules were mainly categorized by the function...
October 28, 2018: Journal of Cellular Physiology
Richa Rani, Sudhir Kumar, Akanksha Sharma, Sujit K Mohanty, Bryan Donnelly, Gregory M Tiao, Chandrashekhar Gandhi
Mice depleted of hepatic stellate cells (HSCs) are protected from concanavalin A (ConA)-induced liver injury that is mediated by the activation of interferon regulatory factor 1 (IRF1). The aim of this study was to determine the mechanisms of ConA-mediated signaling and synthesis/release of mediators by HSCs that damage hepatocytes. Primary cultures of wild type (WT) and IRF1-knockout (KO) HSCs and hepatocytes were used, and ConA-induced liver damage in IFNαβ receptor-deficient (IFNαβR-KO) mice was determined...
October 22, 2018: Journal of Biological Chemistry
Jiawen Qian, Chen Wang, Bo Wang, Jiao Yang, Yuedi Wang, Feifei Luo, Junying Xu, Chujun Zhao, Ronghua Liu, Yiwei Chu
BACKGROUND: PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS: The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model...
October 17, 2018: Journal of Neuroinflammation
Liang-Che Chang, Tzu-Ping Chen, Wei-Ke Kuo, Chung-Ching Hua
Introduction: The expression of programmed death 1 (PD1) and programmed death ligand 1 (PDL1) can be induced by the interferon (IFN)/signal transducer and activator of transcription (STAT) pathway. The PD1/PDL1 reverse signaling can activate the eukaryotic translation initiation factor 2 (eIF2 α )/activating transcription factor 4 (ATF4) pathway which in turn regulates the expression of IFN regulatory factor (IRF) 7 and IFN α . The eIF2 α /ATF4 pathway is responsible for the integrated stress response (ISR) of unfolded protein response (UPR) which can affect immune cell function in tumor microenvironment...
2018: Disease Markers
Viviana Annibali, Renato Umeton, Antonia Palermo, Martina Severa, Marilena Paola Etna, Simona Giglio, Silvia Romano, Michela Ferraldeschi, Maria Chiara Buscarinu, Andrea Vecchione, Anita Annese, Claudia Policano, Rosella Mechelli, Raffaella Pizzolato Umeton, Arianna Fornasiero, Daniela Francesca Angelini, Gisella Guerrera, Luca Battistini, Eliana Marina Coccia, Marco Salvetti, Giovanni Ristori
Several evidences emphasize B-cell pathogenic roles in multiple sclerosis (MS). We performed transcriptome analyses on peripheral B cells from therapy-free patients and age/sex-matched controls. Down-regulation of two transcripts (interferon response factor 1-IRF1, and C-X-C motif chemokine 10-CXCL10), belonging to the same pathway, was validated by RT-PCR in 26 patients and 21 controls. IRF1 and CXCL10 transcripts share potential seeding sequences for hsa-miR-424, that resulted up-regulated in MS patients...
November 15, 2018: Journal of Neuroimmunology
Maikel L Colli, Jessica L E Hill, Laura Marroquí, Jessica Chaffey, Reinaldo S Dos Santos, Pia Leete, Alexandra Coomans de Brachène, Flavia M M Paula, Anne Op de Beeck, Angela Castela, Lorella Marselli, Lars Krogvold, Knut Dahl-Jorgensen, Piero Marchetti, Noel G Morgan, Sarah J Richardson, Décio L Eizirik
BACKGROUND: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. METHODS: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot...
October 2018: EBioMedicine
Kexin Hua, Yaqian Li, Hongjian Chen, Jiamin Ni, Dingren Bi, Rui Luo, Hui Jin
TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) serves as hub molecule at the crossroad of multiple signaling pathways of type I interferon (IFN) induction. The importance of TBK1 in innate immunity has been demonstrated in mammalian, however the characterization and function of TBK1 in avian remains largely unknown. In this study, we cloned duck TBK1 (duTBK1) from duck embryo fibroblasts (DEFs) for the first time, which encoded 729 amino acids and had a high amino acid identity with goose and cormorant TBK1s...
September 27, 2018: Cytokine
Tiantian Gu, Lu Lu, Chen An, Yu Zhang, Xinsheng Wu, Qi Xu, Guohong Chen
Ubiquitin-specific protease 18 (USP18) plays an important role in regulating type I interferon (IFN) signaling in innate immunity, and has a crucial impact on the IFN therapeutic effect. Although significant progress has been made in elucidating USP18 function in mammals, the role of USP18 in ducks (duUSP18) remains poorly understood. In this study, we cloned the USP18 gene from white crested ducks by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of complementary DNA (cDNA) ends...
September 7, 2018: Journal of Cellular Physiology
Jinsheng Liang, Ying Cui, Yuhuan Meng, Xingsong Li, Xueping Wang, Wanli Liu, Lizhen Huang, Hongli Du
Transcription factors are recognized as the key regulators of gene expression. However, the changes in the correlation of transcription factors and their target genes between normal and tumor tissues are usually ignored. In this research, we used mRNA expression profile data from The Cancer Genome Atlas which included 5726 samples across 11 major human cancers to perform co-expression analysis by the Pearson correlation coefficients. Then, integrating 81,357 pairs of transcription factors and target genes from transcription factors databases to find out the changes in the co-expression correlation of these gene pairs from normal to tumor tissues...
September 24, 2018: Functional & Integrative Genomics
Atsushi Shiozaki, Yosuke Ariyoshi, Daisuke Iitaka, Toshiyuki Kosuga, Hiroki Shimizu, Michihiro Kudou, Tomoki Konishi, Katsutoshi Shoda, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Takeshi Kubota, Hitoshi Fujiwara, Kazuma Okamoto, Mitsuo Kishimoto, Eiichi Konishi, Yoshinori Marunaka, Daisuke Ichikawa, Eigo Otsuji
BACKGROUND: Recent studies have described important roles for the sodium iodide symporter (NIS) in tumor behavior. The objectives of the present study were to investigate the role of NIS in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in gastric cancer (GC). METHODS: In human GC cell lines, knockdown experiments were conducted using NIS siRNA, and the effects on proliferation, survival, and cellular movement were analyzed...
September 6, 2018: Gastric Cancer
Kazumi Ebine, Krishan Kumar, Thao N Pham, Mario A Shields, Katharine A Collier, Meng Shang, Brian T DeCant, Raul Urrutia, Rosa F Hwang, Sam Grimaldo, Daniel R Principe, Paul J Grippo, David J Bentrem, Hidayatullah G Munshi
The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells...
September 5, 2018: Scientific Reports
Peiqi Wan, Xiaojv Chi, Qiang Du, Jing Luo, Xiao Cui, Kun Dong, Yan Bing, Caroline Heres, David A Geller
Interferon regulatory factor 1 (IRF1) has been found to serve as a tumor suppressor in cholangiocarcinoma, and enabled prediction of clinical progression and prognosis in our previous study. The objective of the current study is to screen and identify valuable microRNAs (miR), which target IRF1 to regulate cholangiocarcinoma cell proliferation, migration, and invasion. High expression of miR-383 was observed in cholangiocarcinoma tissues and cells. Meanwhile, we found the predicted binding site of miR-383 on the IRF1 3'-untranslated region (3'-UTR) according to the miR target database...
August 26, 2018: Journal of Cellular Biochemistry
Priya Luthra, Jacinth Naidoo, Colette A Pietzsch, Sampriti De, Sudip Khadka, Manu Anantpadma, Caroline G Williams, Megan R Edwards, Robert A Davey, Alexander Bukreyev, Joseph M Ready, Christopher F Basler
Specific host pathways that may be targeted therapeutically to inhibit the replication of Ebola virus (EBOV) and other emerging viruses remain incompletely defined. A screen of 200,000 compounds for inhibition of an EBOV minigenome (MG) assay that measures the function of the viral polymerase complex identified as hits several compounds with an amino-tetrahydrocarbazole scaffold. This scaffold was structurally similar to GSK983, a compound previously described as having broad-spectrum antiviral activity due to its impairing de novo pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase (DHODH)...
October 2018: Antiviral Research
Daniela Bruni, Adam Dignam, Susan Dunne, Devlin Wall-Coughlan, Aisling McCrudden, Karen O'Connell, Caitriona Lyons, Christopher McGuigan, Niall Tubridy, Marion P Butler
IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C)...
October 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
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