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Hanchao Gao, Qing Zhang, Jicheng Chen, David K C Cooper, Hidetaka Hara, Pengfei Chen, Ling Wei, Yanli Zhao, Jia Xu, Zesong Li, Zhiming Cai, Shaodong Luan, Lisha Mou
Whether porcine cytokines are induced after pig-to-primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL-6, IFN-γ, IL-1β, and TNF-α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro-inflammatory cytokines (IL-6, IFN-γ, and IL-1β) and chemokines (IL-8, MCP-1, and CXCL2) were upregulated in the both cell types...
June 22, 2018: Xenotransplantation
Michael J Workman, John P Gleeson, Elissa J Troisi, Hannah Q Estrada, S Jordan Kerns, Christopher D Hinojosa, Geraldine A Hamilton, Stephan R Targan, Clive N Svendsen, Robert J Barrett
Background and Aims: Human intestinal organoids derived from induced pluripotent stem cells have tremendous potential to elucidate the intestinal epithelium's role in health and disease, but it is difficult to directly assay these complex structures. This study sought to make this technology more amenable for study by obtaining epithelial cells from induced pluripotent stem cell-derived human intestinal organoids and incorporating them into small microengineered Chips. We then investigated if these cells within the Chip were polarized, had the 4 major intestinal epithelial subtypes, and were biologically responsive to exogenous stimuli...
2018: Cellular and Molecular Gastroenterology and Hepatology
Minggang Peng, Jingjing Wang, Dongyun Zhang, Honglei Jin, Jingxia Li, Xue-Ru Wu, Chuanshu Huang
Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a tumor suppressor that catalyzes the de-phosphorylation of the AGC kinases, while p27 acts as a tumor suppressor that regulates cell cycle, apoptosis, and cell motility. Our previous studies have identified that PHLPP2 participates in inhibition of transformation of human bronchial epithelial cells following lung carcinogen B[a]P/B[a]PDE exposure. However, nothing was known about the association of p27 with regulation of PHLPP2 expression and the role of PHLPP2 in bladder cancer (BC) invasion...
June 21, 2018: Oncogene
Huan Zhang, Liurong Fang, Xinyu Zhu, Dang Wang, Shaobo Xiao
Protein lysine ubiquitination is a dynamic reversible post-translational modification that plays key roles in modulating different cellular processes. Porcine reproductive and respiratory syndrome virus (PRRSV) is a notorious pathogen, causing tremendous economic losses for the global swine industry. The possible involvement of ubiquitination in PRRSV infection is unclear. So anti-ubiquitination-based enrichment and LC-MS were performed to investigate the global ubiquitination events triggered by PRRSV infection in pulmonary alveolar macrophages...
June 18, 2018: Journal of Proteomics
Yujuan Zhang, Saloni Gupta, Alexandra Ilstad-Minnihan, Sashi Ayyangar, Arielle D Hay, Virginia Pascual, Norman T Ilowite, Claudia Macaubas, Elizabeth D Mellins
Systemic juvenile idiopathic arthritis (sJIA) is a childhood rheumatic disease of unknown origin. Dysregulated innate immunity is implicated in disease pathology. We investigated if IL-1 inhibition affects circulating cytokines and monocyte gene expression. CD14+ monocytes from patients in the RAPPORT trial were analyzed by RT-PCR for expression of IL1B and transcription factors associated with monocyte activation. Serum IL-1ra decreased with treatment, and IL-18BP transiently increased. Serum levels of IL-1β, IL-6, IL-10 and IL-18 were unchanged...
June 18, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Fumihisa Nakamura, Ichiro Tsukamoto, Shinji Inoue, Kazuhiko Hashimoto, Masao Akagi
Angiotensin II type 1 receptor (AT1R) appears to have a mechanosensing function in a number of cell types. The purpose of this study was to examine whether AT1R expressed in articular chondrocytes is involved in osteoarthritis (OA) progression in vivo and whether cyclic compressive loading activates the AT1R and stimulates hypertrophic differentiation of chondrocytes in vitro . The relationships between the modified Mankin score for cartilage degeneration and the expression of AT1R and type X collagen (Col X) were studied in mouse knees with OA induced using the destabilization-of-medial-meniscus model...
June 2018: FEBS Open Bio
Antoine Dufour, Caroline L Bellac, Ulrich Eckhard, Nestor Solis, Theo Klein, Reinhild Kappelhoff, Nikolaus Fortelny, Parker Jobin, Jacob Rozmus, Jennifer Mark, Paul Pavlidis, Vincent Dive, Sean J Barbour, Christopher M Overall
Controlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show a negative feedback mechanism for proinflammatory IFN-γ activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-γ at 135Glu↓Leu136 the IFN-γ receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-γ activation of proinflammatory macrophages...
June 20, 2018: Nature Communications
Giel P Göertz, Kristin L McNally, Shelly J Robertson, Sonja M Best, Gorben P Pijlman, Jelke J Fros
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has evolved effective mechanisms to counteract the type I interferon (IFN) response. Upon viral recognition, cells secrete IFNs which signal through transmembrane receptors (IFNAR) to phosphorylate STAT proteins (pSTAT). pSTAT dimers are transported into the nucleus by importin-α5 and activate the transcription of IFN stimulated genes (ISGs) increasing cellular resistance to infection. Subsequently, STAT proteins are shuttled back into the cytoplasm by exportin CRM1...
June 20, 2018: Journal of Virology
Heeju Ryu, Hoyong Lim, Garam Choi, Young-Jun Park, Minkyoung Cho, Hyeongjin Na, Chul Won Ahn, Young Chul Kim, Wan-Uk Kim, Sang-Hak Lee, Yeonseok Chung
In the version of this article initially published, the third label along the horizontal axis of Fig. 4b (Il13a) and the middle label above each plot in Fig. 6k (Stat-/- ) were incorrect, and the hash marks along the horizontal axis for Fig. 6i were spaced incorrectly. Also, the statistical results in the citation for Supplementary Fig. 5a (*P < 0.05, **P < 0.01 and ***P < 0.001 (unpaired Student's t-test)) in the fifth subsection of Results were incorrect. The correct label for Fig. 4b is Il23a and for Fig...
June 19, 2018: Nature Immunology
Lionel B Ivashkiv
IFNγ is a cytokine with important roles in tissue homeostasis, immune and inflammatory responses and tumour immunosurveillance. Signalling by the IFNγ receptor activates the Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) pathway to induce the expression of classical interferon-stimulated genes that have key immune effector functions. This Review focuses on recent advances in our understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an 'M1-like' state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors...
June 19, 2018: Nature Reviews. Immunology
Shang-Hung Lin, Hung-Yi Chuang, Ji-Chen Ho, Chih-Hung Lee, Chang-Chun Hsiao
BACKGROUND: Psoriasis is a systemic inflammatory disease with dramatic responses to TNF-α inhibitors. TNF-α is mainly produced by macrophages. However, how macrophage polarization contributes to psoriasis remains unknown. OBJECTIVE: We aimed to investigate the molecular mechanisms of macrophage polarization in psoriasis. METHODS: 8 patients with moderate to severe psoriasis (Male/Female: 4/4, average age: 47.9 years old) and 8 healthy controls (Male/Female: 4/4, average age: 49...
May 29, 2018: Journal of Dermatological Science
Zubin Patel, Xiaoming Lu, Daniel Miller, Carmy R Forney, Joshua Lee, Arthur Lynch, Connor Schroeder, Lois Parks, Albert F Magnusen, Xiaoting Chen, Mario Pujato, Avery Maddox, Erin E Zoller, Bahram Namjou, Hermine I Brunner, Michael Henrickson, Jennifer L Huggins, Adrienne H Williams, Julie T Ziegler, Mary E Comeau, Miranda C Marion, Stuart B Glenn, Adam Adler, Nan Shen, Swapan K Nath, Anne M Stevens, Barry I Freedman, Bernardo A Pons-Estel, Betty P Tsao, Chaim O Jacob, Diane L Kamen, Elizabeth E Brown, Gary S Gilkeson, Graciela S Alarcón, Javier Martin, John D Reveille, Juan-Manuel Anaya, Judith A James, Kathy L Sivils, Lindsey A Criswell, Luis M Vilá, Michelle Petri, R Hal Scofield, Robert P Kimberly, Jeffrey C Edberg, Rosalind Ramsey-Goldman, So-Young Bang, Hye-Soon Lee, Sang-Cheol Bae, Susan A Boackle, Deborah Cunninghame Graham, Timothy J Vyse, Joan T Merrill, Timothy B Niewold, Hannah C Ainsworth, Earl D Silverman, Michael H Weisman, Daniel J Wallace, Prithvi Raj, Joel M Guthridge, Patrick M Gaffney, Jennifer A Kelly, Marta E Alarcón-Riquelme, Carl D Langefeld, Edward K Wakeland, Kenneth M Kaufman, Matthew T Weirauch, John B Harley, Leah C Kottyan
Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341...
April 18, 2018: Human Molecular Genetics
Edit Porpaczy, Sabrina Tripolt, Andrea Hoelbl-Kovacic, Bettina Gisslinger, Zsuzsanna Bago-Horvath, Emilio Casanova-Hevia, Emmanuelle Clappier, Thomas Decker, Sabine Fajmann, Daniela A Fux, Georg Greiner, Sinan Gueltekin, Gerwin Heller, Harald Herkner, Gregor Hoermann, Jean-Jacques Kiladjian, Thomas Kolbe, Christoph Kornauth, Maria-Theresa Krauth, Robert Kralovics, Leonhard Muellauer, Mathias Mueller, Michaela Prchal-Murphy, Eva Maria Putz, Emmanuel Raffoux, Ana-Iris Schiefer, Klaus Schmetterer, Christine Schneckenleithner, Ingrid Simonitsch-Klupp, Cathrin Skrabs, Wolfgang R Sperr, Philipp Bernhard Staber, Birgit Strobl, Peter Valent, Ulrich Jaeger, Heinz Gisslinger, Veronika Sexl
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 MPN patients including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4/69 patients (5.8%) upon JAK1/2 inhibition compared to 2/557 (0.36%) with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 MPN patients...
June 14, 2018: Blood
Gabriela Vera-Lozada, Priscilla Segges, Claudio Gustavo Stefanoff, Mário Henrique M Barros, Gerald Niedobitek, Rocio Hassan
The search for clinically relevant molecular markers in classical Hodgkin lymphoma (cHL) is hampered by the histopathological complexity of the disease, resulting from the admixture of a small number of neoplastic Hodgkin and Reed-Sternberg (H-RS) cells with an abundant and heterogeneous microenvironment. In this study, we evaluated gene expression profiles of 11 selected genes previously proposed as a molecular score for adult cHL, aiming to validate its application in the pediatric setting. Assays were performed by RT-qPCR from formalin-fixed paraffin-embedded (FFPE) lymph nodes in 80 patients with cHL...
June 14, 2018: Hematological Oncology
Ashutosh Rai, B D Radotra, K K Mukherjee, S K Gupta, Pinaki Dutta
Here we describe data of a comprehensive phosphoproteomic evaluation of 20 non-functioning pituitary adenomas (NFPAs). Peptides from 20 tumor samples were enriched with TiO2 beads and fractioned using bRPLC and subjected to high throughput LC-MS/MS-Orbitrap Fusion™ Tribrid™ Mass Spectrometer for analysis. Upto 5 precursor ions were selected for MS/MS analysis. Data was analyzed using MASCOT and SEQUEST. Bioinformatics tools Phosphosite Plus, Gene Ontology, DAVID, and KEGG were used to determine the biological significance of identified phosphoproteins...
June 2018: Data in Brief
Tian Zhou, Zijing Huang, Xiaowei Zhu, Xiaowei Sun, Yan Liu, Bing Cheng, Mei Li, Yizhi Liu, Chang He, Xialin Liu
Neurodegenerative diseases are a set of disorders characterized by progressive neuronal death and are associated with microglia-mediated neuroinflammation. Recently, neuroinflammation is proposed as a promising therapeutic target for many neurodegenerative diseases. Alpha-1 antitrypsin (AAT) is recognized as a novel immunomodulatory agent in autoimmune diseases and transplantation, however, its impact on neuroinflammation and neurodegeneration remains unknown. This study aims to explore the effects of AAT on microglia-mediated neuroinflammation and retinal degeneration in rd1 mouse model...
2018: Frontiers in Immunology
Lilli Arndt, Janine Dokas, Martin Gericke, Carl Elias Kutzner, Silvana Müller, Franziska Jeromin, Joachim Thiery, Ralph Burkhardt
Macrophages are essential for innate immunity and inflammatory responses and differentiate into various functional phenotypes. Tribbles homolog 1 ( Trib1 ), a member of the mammalian Tribbles homolog pseudokinase family, has been implicated in regulation of cell differentiation, proliferation and metabolism, but its role in macrophage biology has not been fully elucidated. Here, we investigated the consequences of Trib1 deficiency on macrophage functions and M1/M2 polarization. Bone marrow-derived macrophages (BMDMs) from Trib1 -deficient ( Trib1 -/- ) mice exhibited elevated phagocytic capacity, correlating with up-regulation of several scavenger receptors...
June 13, 2018: Journal of Biological Chemistry
Kosuke Zenke, Masashi Muroi, Ken-Ichi Tanamoto
The signal transducer and activator of transcription 1 (STAT1), a pivotal transcription factor in Janus kinase (JAK)-STAT signaling, regulates the expression of a wide range of immune-related genes, including interferon regulatory factor 1 (IRF1). In this study, we found that IRF1 could induce STAT1 phosphorylation and in turn STAT1 activation. When IRF1 was transiently expressed in HEK293 cells, STAT1 phosphorylated at Y701 dimerized and bound to an oligonucleotide containing a gamma-activated sequence (GAS) derived from the IRF1 promoter...
June 12, 2018: Immunology and Cell Biology
Agata Michalska, Katarzyna Blaszczyk, Joanna Wesoly, Hans A R Bluyssen
Interferon (IFN)-I and IFN-II both induce IFN-stimulated gene (ISG) expression through Janus kinase (JAK)-dependent phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2. STAT1 homodimers, known as γ-activated factor (GAF), activate transcription in response to all types of IFNs by direct binding to IFN-II activation site (γ-activated sequence)-containing genes. Association of interferon regulatory factor (IRF) 9 with STAT1-STAT2 heterodimers [known as interferon-stimulated gene factor 3 (ISGF3)] or with STAT2 homodimers (STAT2/IRF9) in response to IFN-I, redirects these complexes to a distinct group of target genes harboring the interferon-stimulated response element (ISRE)...
2018: Frontiers in Immunology
Satoshi Nakagawa, Satoshi Serada, Reisa Kakubari, Kosuke Hiramatsu, Takahito Sugase, Shinya Matsuzaki, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Tomoharu Ohkawara, Minoru Fujimoto, Tadamitsu Kishimoto, Tadashi Kimura, Tetsuji Naka
Ovarian cancer (OvCa) is the leading cause of gynecological cancer-related deaths and novel therapeutic strategies are required. Programmed cell death 1 and programmed cell death ligand 1 (PD-L1), which are key mediators of host immune tolerance, are associated with OvCa progression. Recent evidence indicates the importance of IFN-γ-induced PD-L1 for immune tolerance in OvCa. This study aimed to reveal the therapeutic potential of suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, for the treatment of OvCa...
June 11, 2018: Molecular Cancer Therapeutics
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