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https://www.readbyqxmd.com/read/27912060/the-hippo-pathway-kinases-lats1-2-suppress-cancer-immunity
#1
Toshiro Moroishi, Tomoko Hayashi, Wei-Wei Pan, Yu Fujita, Matthew V Holt, Jun Qin, Dennis A Carson, Kun-Liang Guan
Poorly immunogenic tumor cells evade host immunity and grow even in the presence of an intact immune system, but the complex mechanisms regulating tumor immunogenicity have not been elucidated. Here, we discovered an unexpected role of the Hippo pathway in suppressing anti-tumor immunity. We demonstrate that, in three different murine syngeneic tumor models (B16, SCC7, and 4T1), loss of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in tumor cells inhibits tumor growth. Tumor regression by LATS1/2 deletion requires adaptive immune responses, and LATS1/2 deficiency enhances tumor vaccine efficacy...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27908440/lipid-raft-dependent-endocytosis-negatively-regulates-responsiveness-of-j774-macrophage-like-cells-to-lps-by-down-regulating-the-cell-surface-expression-of-lps-receptors
#2
Szczepan Józefowski, Małgorzata Śróttek
Acting through CD14 and TLR4/MD-2, lipopolysaccharide (LPS) triggers strong pro-inflammatory activation of macrophages, which, if not appropriately controlled, may lead to lethal septic shock. Therefore, numerous mechanisms of negative regulation of responses to LPS exist, but whether they include down-regulation of LPS receptors is not clear. We have found that in J774 cells, the clathrin-dependent endocytic pathway enables activation of TRIF-dependent TLR4 signaling within endosomes, but is not associated with the down-regulation of TLR4 or CD14 surface expression...
November 23, 2016: Cellular Immunology
https://www.readbyqxmd.com/read/27891130/molecular-mechanisms-that-underlie-the-dynamic-adaptation-of-innate-monocyte-memory-to-varying-stimulant-strength-of-tlr-ligands
#3
Ruoxi Yuan, Shuo Geng, Liwu Li
In adaptation to rising stimulant strength, innate monocytes can be dynamically programed to preferentially express either pro- or anti-inflammatory mediators. Such dynamic innate adaptation or programing may bear profound relevance in host health and disease. However, molecular mechanisms that govern innate adaptation to varying strength of stimulants are not well understood. Using lipopolysaccharide (LPS), the model stimulant of toll-like-receptor 4 (TLR4), we reported that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by lower doses of LPS, and suppressed/tolerized in monocytes adapted by higher doses of LPS...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27881733/lysosomal-trafficking-regulator-lyst-links-membrane-trafficking-to-toll-like-receptor-mediated-inflammatory-responses
#4
Andreas Westphal, Weijia Cheng, Jinbo Yu, Guntram Grassl, Martina Krautkrämer, Otto Holst, Niko Föger, Kyeong-Hee Lee
Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)- and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27872207/myeloid-specific-gene-deletion-of-protein-phosphatase-2a-magnifies-myd88-and-trif-dependent-inflammation-following-endotoxin-challenge
#5
Lei Sun, Tiffany T Pham, Timothy T Cornell, Kelli L McDonough, Walker M McHugh, Neal B Blatt, Mary K Dahmer, Thomas P Shanley
Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells...
November 21, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27862204/a-comparison-of-the-immunological-potency-of-burkholderia-lipopolysaccharides-in-endotoxemic-balb-c-mice
#6
Pei-Tan Hsueh, Chiu-Lin Liu, Hsuan-Han Wang, Wei-Fen Ni, Ya-Lei Chen, Jong-Kang Liu
Lipopolysaccharide is one of the virulence factors of the soil-borne pathogens Burkholderia pseudomallei, B. thailandensis, B. cenocepacia and B. multivorans, which cause septic melioidosis (often in B. pseudomallei infections but rarely in B. thailandensis infections) or cepacia syndromes (commonly in B. cenocepacia infections but rarely in B. multivorans infections). The inflammatory responses in Burkholderia LPS-induced endotoxemia were evaluated in this study. Prior to induction, the conserved structures and functions of each purified LPS were determined using electrophoretic phenotypes, the ratios of 3-hydroxytetradecanoic to 3-hydroxyhexadecanoic acid and endotoxin units...
November 2016: Microbiology and Immunology
https://www.readbyqxmd.com/read/27853628/tir-domain-containing-adapter-inducing-interferon-%C3%AE-trif-regulates-cxcr5-t-helper-cells-in-the-intestine
#7
Saravana Kanagavelu, Claudia Flores, Shinichiro Hagiwara, Jose Ruiz, Jinhee Hyun, Ei E Cho, Frank Sun, Laura Romero, David Q Shih, Masayuki Fukata
OBJECTIVE: Establishing an effective humoral immunity is an important host defense mechanism in intestinal mucosa. T follicular helper (Tfh) cells are a spectrum of CXCR5 expressing T helper cells that induce antigen-specific B cell differentiation. Because the differentiation of T helper cells is largely regulated by innate immunity, we addressed whether TRIF signaling regulates Tfh cell differentiation and its ability to trigger humoral immune responses in the intestine. METHOD: CD4(+)CXCR5(+) T cells, B cells, and plasma cells in the Peyer's patches (PPs) of WT and TRIF-deficient (Trif(LPS2)) mice were analyzed by flow cytometry at the baseline, 9 days post primary infection, and 7 days post-secondary infection with Y...
October 2016: Journal of Clinical & Cellular Immunology
https://www.readbyqxmd.com/read/27847343/fish-trim32-functions-as-a-critical-antiviral-molecule-against-iridovirus-and-nodavirus
#8
Yepin Yu, Xiaohong Huang, Jiaxin Liu, Jingcheng Zhang, Yin Hu, Ying Yang, Youhua Huang, Qiwei Qin
Tripartite motif-containing 32 (TRIM32) has been demonstrated to pay vital roles in cancer, genetic disorders and antiviral immunity. However, the molecular functions of fish TRIM32 still remained largely unknown. Here, a novel TRIM32 gene from orange spotted grouper (EcTRIM32) was cloned and characterized. EcTRIM32 encoded a 685-aa protein which showed 93%, and 60% identity to large yellow croaker (Larimichthys crocea) and human (Homo sapiens), respectively. Amino acid alignment showed that EcTRIM32 contained a conserved RING-finger domain, a BBOX domain and NHL domain...
November 12, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27830882/histological-changes-in-the-vulva-and-vagina-from-ovariectomised-rats-undergoing-oestrogen-treatment
#9
Radu Florin Mocan-Hognogi, Nicolae Costin, Andrei Malutan, Razvan Ciortea, Ioana Alexandra Trif, Andras Laszlo Nagy, Marian Liviu Bogdan, Dan Mihu
BACKGROUND: The purpose of this study was to assess the histological changes occurring in the vagina and vulva in ovariectomised female rats, as well as the response to the administration of injectable oestrogens. MATERIAL AND METHODS: We used 30 female Wistar white rats, distributed as follows: group 1 - the control group, group 2 - the operated but untreated rats, and groups 3, 4 and 5, operated rats, to which oestrogenic treatment was administered (Estradiol, Estradurin, Sintofolin), at a dosage of 0...
November 10, 2016: Folia Morphologica (Warsz)
https://www.readbyqxmd.com/read/27810900/endoplasmic-reticulum-stress-induced-hepatocellular-death-pathways-mediate-liver-injury-and-fibrosis-via-stimulator-of-interferon-genes
#10
Arvin Iracheta-Vellve, Jan Petrasek, Benedek Gyongyosi, Abhishek Satishchandran, Patrick Lowe, Karen Kodys, Donna Catalano, Charles D Calenda, Evelyn A Kurt-Jones, Katherine A Fitzgerald, Gyongyi Szabo
Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon Regulatory Factor 3 (IRF3) regulates hepatocyte apoptosis and production of Type-I interferons (IFNs). In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the ER adapter, Stimulator of Interferon Genes (STING)...
November 3, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27755506/sting-and-trif-contribute-to-mouse-sepsis-depending-on-severity-of-the-disease-model
#11
Erica L Heipertz, Jourdan Harper, Wendy E Walker
IFN regulatory factor (IRF)3 plays a detrimental role in the cecal ligation and puncture (CLP) mouse model of sepsis. However, it is unclear which pathway activates IRF3 in this context. In this report we investigate two pathways that activate IRF3: the Stimulator of Interferon Genes (STING) pathway (which senses cytosolic DNA) and the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway (which sense dsRNA and LPS via Toll-like receptor (TLR) 3 and 4). Initially, we examine the impact of these pathways using a severe CLP model (∼90% mortality)...
October 17, 2016: Shock
https://www.readbyqxmd.com/read/27748405/disabled-2-is-a-negative-immune-regulator-of-lipopolysaccharide-stimulated-toll-like-receptor-4-internalization-and-signaling
#12
Wei-Shan Hung, Pin Ling, Ju-Chien Cheng, Shy-Shin Chang, Ching-Ping Tseng
Toll-like receptor 4 (TLR4) plays a pivotal role in the host response to lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Here, we elucidated whether the endocytic adaptor protein Disabled-2 (Dab2), which is abundantly expressed in macrophages, plays a role in LPS-stimulated TLR4 signaling and trafficking. Molecular analysis and transcriptome profiling of RAW264.7 macrophage-like cells expressing short-hairpin RNA of Dab2 revealed that Dab2 regulated the TLR4/TRIF pathway upon LPS stimulation...
October 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27733552/cell-extrinsic-tnf-collaborates-with-trif-signaling-to-promote-yersinia-induced-apoptosis
#13
Lance W Peterson, Naomi H Philip, Christopher P Dillon, John Bertin, Peter J Gough, Douglas R Green, Igor E Brodsky
Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27716849/increased-cd40-expression-enhances-early-sting-mediated-type-i-interferon-response-and-host-survival-in-a-rodent-malaria-model
#14
Xiangyu Yao, Jian Wu, Meng Lin, Wenxiang Sun, Xiao He, Channe Gowda, Silvia Bolland, Carole A Long, Rongfu Wang, Xin-Zhuan Su
Both type I interferon (IFN-I) and CD40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. CD40 is mostly known to function in adaptive immunity, but previous observations of elevated CD40 levels early after malaria infection of mice led us to investigate its roles in innate IFN-I responses and disease control. Using a Plasmodium yoelii nigeriensis N67 and C57BL/6 mouse model, we showed that infected CD40-/- mice had reduced STING and serum IFN-β levels day-2 post infection, higher day-4 parasitemia, and earlier deaths...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27689757/mechanisms-underlying-the-hyperalgesic-responses-triggered-by-joint-activation-of-tlr4
#15
Ana T G Guerrero, Larissa G Pinto, Fernando Q Cunha, Sérgio H Ferreira, Jose C Alves-Filho, Waldiceu A Verri, Thiago M Cunha
BACKGROUND: Toll-like receptors (TLRs) including TLR4 and their signal pathways contribute to the pathogenesis of arthritis. Herein, we evaluated the mechanisms underlying the hyperalgesic response caused by TLR4 activation in the tibio-tarsal joint in mice. METHODS: Joint inflammatory hyperalgesia was induced by intra-articular (ia) injection of LPS (lipopolysaccharide- TLR4 agonist) in C57BL/6, TLR4, TLR2, MyD88, TRIF, TNFR1/2 and IL-1R1 knockout ((-/-)) mice...
August 24, 2016: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/27688705/lps-induced-expression-of-cd14-in-the-trif-pathway-is-epigenetically-regulated-by-sulforaphane-in-porcine-pulmonary-alveolar-macrophages
#16
Qin Yang, Maren J Pröll, Dessie Salilew-Wondim, Rui Zhang, Dawit Tesfaye, Huitao Fan, Mehmet U Cinar, Christine Große-Brinkhaus, Ernst Tholen, Mohammad A Islam, Michael Hölker, Karl Schellander, Muhammad J Uddin, Christiane Neuhoff
Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN...
September 29, 2016: Innate Immunity
https://www.readbyqxmd.com/read/27659428/prevention-of-allograft-rejection-in-heart-transplantation-through-concurrent-gene-silencing-of-tlr-and-kinase-signaling-pathways
#17
Hongmei Wang, Xusheng Zhang, Xiufen Zheng, Zhu Lan, Jun Shi, Jifu Jiang, Terry Zwiep, Qing Li, Douglas Quan, Zhu-Xu Zhang, Weiping Min
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27631700/sting-requires-the-adaptor-trif-to-trigger-innate-immune-responses-to-microbial-infection
#18
Xin Wang, Tanmay Majumdar, Patricia Kessler, Evgeny Ozhegov, Ying Zhang, Saurabh Chattopadhyay, Sailen Barik, Ganes C Sen
The intracellular microbial nucleic acid sensors, TLR3 and STING, recognize pathogen molecules and signal to activate the interferon pathway. The TIR-domain containing protein TRIF is the sole adaptor of TLR3. Here, we report an essential role for TRIF in STING signaling: various activators of STING could not induce genes in the absence of TRIF. TRIF and STING interacted directly, through their carboxy-terminal domains, to promote STING dimerization, intermembrane translocation, and signaling. Herpes simplex virus (HSV), which triggers the STING signaling pathway and is controlled by it, replicated more efficiently in the absence of TRIF, and HSV-infected TRIF(-/-) mice displayed pronounced pathology...
September 14, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27631696/no-trifling-matter-on-sting
#19
Gil Ju Seo, Younho Choi, Jae U Jung
STING is a crucial component of the mammalian innate immune response to microbial infection. In this issue of Cell Host & Microbe, Wang et al. (2016) report that TRIF, an adaptor of Toll-like receptors (TLRs), is essential for STING-mediated innate antiviral immunity as well as pro-protozoal responses.
September 14, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27622031/tlr4-mediated-immunomodulatory-properties-of-the-bacterial-metalloprotease-arazyme-in-preclinical-tumor-models
#20
Felipe V Pereira, Amanda C L Melo, Filipe M de Melo, Diego Mourão-Sá, Priscila Silva, Rodrigo Berzaghi, Carolina C A Herbozo, Jordana Coelho-Dos-Reis, Jorge A Scutti, Clarice S T Origassa, Rosana M Pereira, Luis Juliano, Maria Aparecida Juliano, Adriana K Carmona, Niels O S Câmara, Moriya Tsuji, Luiz R Travassos, Elaine G Rodrigues
Despite the recent approval of new agents for metastatic melanoma, its treatment remains challenging. Moreover, few available immunotherapies induce a strong cellular immune response, and selection of the correct immunoadjuvant is crucial for overcoming this obstacle. Here, we studied the immunomodulatory properties of arazyme, a bacterial metalloprotease, which was previously shown to control metastasis in a murine melanoma B16F10-Nex2 model. The antitumor activity of arazyme was independent of its proteolytic activity, since heat-inactivated protease showed comparable properties to the active enzyme; however, the effect was dependent on an intact immune system, as antitumor properties were lost in immunodeficient mice...
July 2016: Oncoimmunology
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