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https://www.readbyqxmd.com/read/29133930/plc%C3%AE-dependent-mtor-signalling-controls-il-7-mediated-early-b-cell-development
#1
Mei Yu, Yuhong Chen, Hu Zeng, Yongwei Zheng, Guoping Fu, Wen Zhu, Ulrich Broeckel, Praful Aggarwal, Amy Turner, Geoffrey Neale, Cliff Guy, Nan Zhu, Hongbo Chi, Renren Wen, Demin Wang
The precise molecular mechanism underlying the regulation of early B cell lymphopoiesis is unclear. The PLCγ signaling pathway is critical for antigen receptor-mediated lymphocyte activation, but its function in cytokine signaling is unknown. Here we show that PLCγ1/PLCγ2 double deficiency in mice blocks early B cell development at the pre-pro-B cell stage and renders B cell progenitors unresponsive to IL-7. PLCγ pathway inhibition blocks IL-7-induced activation of mTOR, but not Stat5. The PLCγ pathway activates mTOR through the DAG/PKC signaling branch, independent of the conventional Akt/TSC/Rheb signaling axis...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29123954/exogenous-lipid-uptake-induces-metabolic-and-functional-reprogramming-of-tumor-associated-myeloid-derived-suppressor-cells
#2
Amir A Al-Khami, Liqin Zheng, Luis Del Valle, Fokhrul Hossain, Dorota Wyczechowska, Jovanny Zabaleta, Maria D Sanchez, Matthew J Dean, Paulo C Rodriguez, Augusto C Ochoa
Myeloid-derived suppressor cells (MDSC) promote tumor growth by blocking anti-tumor T cell responses. Recent reports show that MDSC increase fatty acid uptake and fatty acid oxidation (FAO) to support their immunosuppressive functions. Inhibition of FAO promoted a therapeutic T cell-mediated anti-tumor effect. Here, we sought to determine the mechanisms by which tumor-infiltrating MDSC increase the uptake of exogenous lipids and undergo metabolic and functional reprogramming to become highly immunosuppressive cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123113/talen-mediated-functional-correction-of-human-ipsc-derived-macrophages-in-context-of-hereditary-pulmonary-alveolar-proteinosis
#3
Alexandra Kuhn, Mania Ackermann, Claudio Mussolino, Toni Cathomen, Nico Lachmann, Thomas Moritz
Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs)...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29121519/iguratimod-ameliorates-inflammatory-responses-by-modulating-the-th17-treg-paradigm-in-dextran-sulphate-sodium-induced-murine-colitis
#4
Xue-Pei Jiang, Xie-Lin Huang, Zao-Peng Yang, Shun-Cai Wang, Wei Xie, Lei Miao, Li Tang, Zhi-Ming Huang
Inflammatory bowel disease (IBD) is an autoimmune disease with an abnormal and persistent immune response. Iguratimod, a novel anti-rheumatic drug, exhibits anti-inflammatory effects and regulates immune response. The role of iguratimod in intestinal mucosal inflammation and immunity has not been examined. The aim of this study was to investigate whether iguratimod ameliorates dextran sulphate sodium (DSS)-induced murine colitis and its potential regulatory mechanism. Murine colitis was induced by administering 2...
November 6, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29118272/beyond-cancer-genes-colorectal-cancer-as-robust-intrinsic-states-formed-by-molecular-interactions
#5
Ruoshi Yuan, Suzhan Zhang, Jiekai Yu, Yanqin Huang, Demin Lu, Runtan Cheng, Sui Huang, Ping Ao, Shu Zheng, Leroy Hood, Xiaomei Zhu
Colorectal cancer (CRC) has complex pathological features that defy the linear-additive reasoning prevailing in current biomedicine studies. In pursuing a mechanistic understanding behind such complexity, we constructed a core molecular-cellular interaction network underlying CRC and investigated its nonlinear dynamical properties. The hypothesis and modelling method has been developed previously and tested in various cancer studies. The network dynamics reveal a landscape of several attractive basins corresponding to both normal intestinal phenotype and robust tumour subtypes, identified by their different molecular signatures...
November 2017: Open Biology
https://www.readbyqxmd.com/read/29115375/persistent-stat5-mediated-ros-production-and-involvement-of-aberrant-p53-apoptotic-signaling-in-the-resistance-of-chronic-myeloid-leukemia-to-imatinib
#6
Yanhong Cheng, Yingchan Hao, Aimei Zhang, Chaojie Hu, Xiaoxiao Jiang, Quan Wu, Xiucai Xu
The persistent activation of signal transducer and activator of transcription 5 (STAT5) may principally be attributed to breakpoint cluster region (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1), and have multi-faceted effects in the development of chronic myeloid leukemia (CML). The p53 protein network regulates important mechanisms in DNA damage repair, cell cycle regulation/checkpoints, and cell senescence and apoptosis, as demonstrated by its ability to positively regulate the expression of various pro-apoptotic genes, including B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax)...
October 20, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29111497/effects-of-growth-hormone-on-uncoupling-protein-1-in-white-adipose-tissues-in-obese-mice
#7
Misa Hayashi, Kumi Futawaka, Rie Koyama, Yue Fan, Midori Matsushita, Asuka Hirao, Yuki Fukuda, Ayako Nushida, Syoko Nezu, Tetsuya Tagami, Kenji Moriyama
OBJECTIVE: The transition of white adipocytes to beige cells (a phenomenon referred to as browning or beigeing) during obesity has been previously reported. Our study aimed to examine the mechanisms through which obesity induced by a high fat diet (HFD) affects uncoupling protein 1 (UCP1) expression via signal transduction and activator of transcription 5 (STAT5s). DESIGN: Seven-week-old male C57BL/6J mice were fed a normal or HFD for 11weeks. Body weight, white adipose tissue weight, and blood lipid and glucose levels were measured...
October 24, 2017: Growth Hormone & IGF Research
https://www.readbyqxmd.com/read/29111217/ruxolitinib-partially-reverses-functional-nk-cell-deficiency-in-patients-with-stat1-gain-of-function-mutations
#8
Alexander Vargas-Hernandez, Emily M Mace, Ofer Zimmerman, Christa S Zerbe, Alexandra F Freeman, Sergio Rosenzweig, Jennifer W Leiding, Troy Torgerson, Matthew C Altman, Edith Schussler, Charlotte Cunningham-Rundles, Ivan K Chinn, Alexandre F Carisey, Imelda C Hanson, Nicholas L Rider, Steven M Holland, Jordan S Orange, Lisa R Forbes
BACKGROUND: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in STAT1 GOF patients. METHODS: NK cell phenotype and function were determined in 16 STAT1 GOF patients...
October 27, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29109234/maresin-1-promotes-inflammatory-resolution-neuroprotection-and-functional-neurological-recovery-after-spinal-cord-injury
#9
Isaac Francos Quijorna, Eva Santos-Nogueira, Karsten Gronert, Aaron B Sullivan, Marcel A Kopp, Benedikt Brommer, Samuel David, Jan M Schwab, Ruben Lopez Vales
Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodelling, and leads to functional deficits. Effective treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized pro-resolving mediators (SPM) hosting potent anti-inflammatory and pro-resolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice...
November 3, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29105654/critical-functions-for-stat5-tetramers-in-the-maturation-and-survival-of-natural-killer-cells
#10
Jian-Xin Lin, Ning Du, Peng Li, Majid Kazemian, Tesfay Gebregiorgis, Rosanne Spolski, Warren J Leonard
Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a-Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8(+) T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29104576/interleukin-7-induces-osteoclast-formation-via-stat5-independent-of-receptor-activator-of-nf-kappab-ligand
#11
Jin-Hee Kim, Ji Hyun Sim, Sunkyung Lee, Min A Seol, Sang-Kyu Ye, Hyun Mu Shin, Eun Bong Lee, Yun Jong Lee, Yun Jung Choi, Wan-Hee Yoo, Jin Hyun Kim, Wan-Uk Kim, Dong-Sup Lee, Jin-Hong Kim, Insoo Kang, Seong Wook Kang, Hang-Rae Kim
Interleukin-7 (IL-7), which is required for the development and survival of T cells in the thymus and periphery, plays a role in joint destruction. However, it remains unclear how IL-7 affects osteoclast formation. Thus, we investigated the mechanism by which IL-7 induced osteoclast formation through IL-7 receptor α (IL-7Rα) in osteoclast precursors. We cultured peripheral blood mononuclear cells or synovial fluid mononuclear cells with IL-7 in the presence or absence of an appropriate inhibitor to analyze osteoclast formation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29100302/a-tyrosine-kinase-stat5-mir21-pdcd4-regulatory-axis-in-chronic-and-acute-myeloid-leukemia-cells
#12
Anne-Sophie Espadinha, Valérie Prouzet-Mauléon, Stéphane Claverol, Valérie Lagarde, Marc Bonneu, François-Xavier Mahon, Bruno Cardinaud
MicroRNAs (miRNAs) are regulators of several key patho-physiological processes, including cell cycle and apoptosis. Using microarray-based miRNA profiling in K562 cells, a model of chronic myeloid leukemia (CML), we found that the oncoprotein BCR-ABL1 regulates the expression of miR-21, an "onco-microRNA", found to be overexpressed in several cancers. This effect relies on the presence of two STAT binding sites on the promoter of miR-21, and on the phosphorylation status of STAT5, a transcription factor activated by the kinase activity of BCR-ABL1...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29097254/interleukin-15-derived-from-guanylin-gc-c-expressing-macrophages-inhibits-fatty-acid-synthase-in-adipocytes
#13
Sayaka Akieda-Asai, Takanori Ida, Mikiya Miyazato, Kenji Kangawa, Yukari Date
Recently we found that guanylin (Gn) and its receptor, guanylyl cyclase C (GC-C), are uniquely expressed in the mesenteric macrophages of some diet-resistant rats and that double-transgenic (dTg) rats overexpressing Gn and GC-C in macrophages demonstrate reduced fatty acid synthase and fat accumulation in fat tissue even when fed a high-fat diet (HFD). Lipid accumulation and fatty acid synthase mRNA levels in cocultured dTg rat adipocytes and macrophages were reduced compared with those in adipocytes cultured with WT rat macrophages...
October 31, 2017: Peptides
https://www.readbyqxmd.com/read/29081404/socs1-regulates-senescence-and-ferroptosis-by-modulating-the-expression-of-p53-target-genes
#14
Emmanuelle Saint-Germain, Lian Mignacca, Mathieu Vernier, Diwakar Bobbala, Subburaj Ilangumaran, Gerardo Ferbeyre
The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis...
October 28, 2017: Aging
https://www.readbyqxmd.com/read/29078395/stat5-mediated-chromatin-interactions-in-superenhancers-activate-il-2-highly-inducible-genes-functional-dissection-of-the-il2ra-gene-locus
#15
Peng Li, Suman Mitra, Rosanne Spolski, Jangsuk Oh, Wei Liao, Zhonghui Tang, Fei Mo, Xingwang Li, Erin E West, Daniel Gromer, Jian-Xin Lin, Chengyu Liu, Yijun Ruan, Warren J Leonard
Cytokines critically control immune responses, but how regulatory programs are altered to allow T cells to differentially respond to distinct cytokine stimuli remains poorly understood. Here, we have globally analyzed enhancer elements bound by IL-2-activated STAT5 and IL-21-activated STAT3 in T cells and identified Il2ra as the top-ranked gene regulated by an IL-2-activated STAT5-bound superenhancer and one of the top genes regulated by STAT3-bound superenhancers. Moreover, we found that STAT5 binding was rapidly superenriched at genes highly induced by IL-2 and that IL-2-activated STAT5 binding induces new and augmented chromatin interactions within superenhancer-containing genes...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29070831/inhibition-of-lobuloalveolar-development-by-foxc1-overexpression-in-the-mouse-mammary-gland
#16
Bowen Gao, Ying Qu, Bingchen Han, Yoshiko Nagaoka, Makoto Katsumata, Nan Deng, Shikha Bose, Liting Jin, Armando E Giuliano, Xiaojiang Cui
The forkhead box transcription factor FOXC1 plays a critical role in embryogenesis and the development of many organs. Its mutations and high expression are associated with many human diseases including breast cancer. Although FOXC1 knockout mouse studies showed that it is not required for mammary gland development during puberty, it is not clear whether its overexpression alters normal mammary development in vivo. To address this question, we generated transgenic mice with mammary-specific FOXC1 overexpression...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29070774/bone-marrow-endothelial-cells-induce-immature-and-mature-b-cell-egress-in-response-to-erythropoietin
#17
Takeshi Ito, Yoko Hamazaki, Akifumi Takaori-Kondo, Nagahiro Minato
Bone marrow stromal cells, including endothelial cells and mesenchymal stromal cells, support the maintenance, differentiation, and retention of hematopoietic stem and precursor cells under steady state conditions. At the onset of an emergency, such as severe blood loss or infection, the status of hematopoiesis in the bone marrow changes rapidly to ensure efficient production of cells of specific lineages; however, the function of stromal cells in emergency hematopoiesis has not been fully elucidated. Here, we unexpectedly found that B precursor, mature B, and T cells were released from the bone marrow into the blood circulation in the early phase of hemorrhagic anemia and phenylhydrazine-induced hemolytic anemia...
October 25, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/29066190/identification-of-new-shikonin-derivatives-as-stat3-inhibitors
#18
Han-Yue Qiu, Jiang-Yan Fu, Min-Kai Yang, Hong-Wei Han, Peng-Fei Wang, Ya-Han Zhang, Hong-Yan Lin, Cheng-Yi Tang, Jin-Liang Qi, Rong-Wu Yang, Xiao-Ming Wang, Hai-Liang Zhu, Yong-Hua Yang
The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins...
October 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29062038/the-src-family-kinase-lck-cooperates-with-oncogenic-flt3-itd-in-cellular-transformation
#19
Alissa Marhäll, Julhash U Kazi, Lars Rönnstrand
The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector...
October 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29059618/development-of-a-robust-reporter-gene-based-assay-for-the-bioactivity-determination-of-il-5-targeted-therapeutic-antibodies
#20
Zhihao Fu, Chuanfei Yu, Lan Wang, Kai Gao, Gangling Xu, Wenbo Wang, Junxia Cao, Junzhi Wang
Eosinophilic asthma is characterized by the eosinophilic inflammation with the allergen independent activation of Th2 lymphocytes. Since IL-5 plays an important role in the maturation, survival and migration of eosinophils, hence the pathogenesis of eosinophilic asthma, biotherapeutics targeting IL-5/IL-5Rα have been developed and/or marketed, including Mepolizumab, Reslizumab, and Benralizumab. Accurate determination of bioactivity is crucial for the safety and efficacy of therapeutic antibodies. The current mode of action (MOA) based method used in the quality control and stability tests for anti-IL-5 mAbs is anti-proliferation assay, which is tedious with long duration and high variation...
September 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
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