RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
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Nonredundant Roles of TIRAP and Myd88 in Airway Response to Endotoxin, Independent of TRIF, IL-1 and IL-18 Pathways
Laboratory Investigation (2006) 86, 1126–1135 & 2006 USCAP, Inc All rights reserved 0023-6837/06 $30.00 www.laboratoryinvestigation.org Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways Dieudonne´e Togbe1, Gorse Aurore1, Nicolas Noulin1,2, Vale´rie FJ Quesniaux1, Silvia Schnyder-Candrian1, Bruno Schnyder1, Virginie Vasseur1, Shizuo Akira3, Kasper Hoebe4, Bruce Beutler4, Bernhard Ryffel1,* and Isabelle Couillin1,* 1Molecular Immunology and Embryology, CNRS UMR6218, Transgenose Institute, Orleans, France; 2R&D Department, Key-Obs, Orleans, France; 3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan and 4Department of Immunology, Scripps Research Institute, La Jolla, CA, USA Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstric- tion and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable. -
Signaling Molecules§ Erin E
Veterinary Immunology and Immunopathology 112 (2006) 302–308 www.elsevier.com/locate/vetimm Short communication Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-4) signaling molecules§ Erin E. Connor a, Elizabeth A. Cates a,b, John L. Williams c, Douglas D. Bannerman a,* a Bovine Functional Genomics Laboratory, U.S. Department of Agriculture, Agricultural Research Service, Beltsville, MD 20705, USA b University of Maryland, College Park, MD 20742, USA c Roslin Institute (Edinburgh), Roslin, Midlothian, Scotland, UK Received 17 January 2006; accepted 7 March 2006 Abstract Toll-like receptor (TLR)-4 is a transmembrane receptor for lipopolysaccharide, a highly pro-inflammatory component of the outer membrane of Gram-negative bacteria. To date, molecules of the TLR-4 signaling pathway have not been well characterized in cattle. The goal of this study was to clone and sequence the full-length coding regions of bovine genes involved in TLR-4 signaling including CASP8, IRAK1, LY96 (MD-2), TICAM2, TIRAP, TOLLIP and TRAF 6 and to position these genes, as well as MyD88 and TICAM1, on the bovine genome using radiation hybrid mapping. Results of this work indicate differences with a previously published bovine sequence for LY96 and a predicted sequence in the GenBank database for TIRAP based on the most recent assembly of the bovine genome. In addition, discrepancies between actual and predicted chromosomal map positions based on the Btau_2.0 genome assembly release were identified, although map positions were consistent with predicted locations based on the current bovine-human comparative map. Alignment of the bovine amino acid sequences with human and murine sequences showed a broad range in conservation, from 52 to 93%. -
Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis
biology Review Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis Goncalo Barreto 1,2,* , Mikko Manninen 3 and Kari K. Eklund 1,2,3 1 Department of Rheumatology, Helsinki University and Helsinki University Hospital, 00014 Helsinki, Finland; kari.eklund@hus.fi 2 Translational Immunology Research Program, University of Helsinki, 00014 Helsinki, Finland 3 Orton Research Institute, 00280 Helsinki, Finland; mikko.manninen@orton.fi * Correspondence: goncalo.barreto@helsinki.fi; Tel.: +358-4585-381-10 Received: 24 February 2020; Accepted: 28 March 2020; Published: 30 March 2020 Abstract: Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs). Keywords: osteoarthritis; chondrocytes; toll-like receptors; apoptosis; innate immunity; cartilage 1. Introduction: The Role of Immunity in OA Clinical osteoarthritis (OA) is preceded by a preclinical stage, which, in conjunction with the presence of risk factors and/or other pathological factors, proceeds to the radiographic OA state. -
Dissecting Negative Regulation of Toll-Like Receptor Signaling
Review Dissecting negative regulation of Toll-like receptor signaling 1,2 1,2 1,2 Takeshi Kondo , Taro Kawai and Shizuo Akira 1 Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan 2 Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Toll-like receptors (TLRs) sense invading microbial pathogens. MyD88 is recruited to all TLRs except for pathogens and play crucial roles in the activation of TLR3 and associates with IL-1R-associated kinases (IRAKs) innate and adaptive immunity. However, excessive and TNFR-associated factor 6 (TRAF6), resulting in activa- TLR activation can disrupt immune homeostasis, and tion of canonical inhibitor of kappa light polypeptide gene may be responsible for the development of autoimmune enhancer in B-cells, kinases (IKKs) (IKKa and IKKb) and and inflammatory diseases. As such, the molecules and nuclear factor (NF)-kBs (Figure 1). In contrast, TRIF is pathways that negatively control TLR signaling have recruited to TLR3 and TLR4, leading to activation of been intensively investigated. Here, we discuss recent NF-kB as well as noncanonical IKKs (TRAF-family- insights into the negative regulation of TLR signaling, member-associated NF-kB activator (TANK) binding kinase with focus on three major mechanisms: (i) dissociation 1 (TBK1) and IKKi) and interferon (IFN) regulatory factor of adaptor complexes; (ii) degradation of signal proteins; (IRF)3 via TRAF proteins (Figure 2). TIRAP functions as a and (iii) transcriptional regulation. We also highlight sorting adapter that recruits MyD88 to TLR2 and TLR4, how pathogens negatively target TLR signaling as a whereas TRAM functions as a bridge adapter between TLR4 strategy to evade the host immune response. -
Dephosphorylating TRAM TRIF-Dependent TLR4 Pathway by Phosphatase PTPN4 Preferentially Inhibits
Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM This information is current as Wanwan Huai, Hui Song, Lijuan Wang, Bingqing Li, Jing of September 29, 2021. Zhao, Lihui Han, Chengjiang Gao, Guosheng Jiang, Lining Zhang and Wei Zhao J Immunol published online 30 March 2015 http://www.jimmunol.org/content/early/2015/03/28/jimmun ol.1402183 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 30, 2015, doi:10.4049/jimmunol.1402183 The Journal of Immunology Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM Wanwan Huai,* Hui Song,* Lijuan Wang,† Bingqing Li,‡ Jing Zhao,* Lihui Han,* Chengjiang Gao,* Guosheng Jiang,‡ Lining Zhang,* and Wei Zhao* TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. -
Bacterial Interactions with Cells of the Intestinal Mucosa: Toll- 1182 Like Receptors and Nod2
Recent advances in basic science BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL- 1182 LIKE RECEPTORS AND NOD2 ECario Gut: first published as on 11 July 2005. Downloaded from Gut 2005;54:1182–1193. doi: 10.1136/gut.2004.062794 SUMMARY Toll-like receptors (TLR) and NOD2 are emerging as key mediators of innate host defence in the intestinal mucosa, crucially involved in maintaining mucosal as well as commensal homeostasis. Recent observations suggest new (patho-) physiological mechanisms of how functional versus dysfunctional TLRx/NOD2 pathways may oppose or favour inflammatory bowel disease (IBD). In Published online first 19 April 2005 health, TLRx signalling protects the intestinal epithelial barrier and confers commensal tolerance whereas NOD2 signalling exerts antimicrobial activity and prevents pathogenic invasion. In disease, aberrant TLRx and/or NOD2 signalling may stimulate diverse inflammatory responses leading to acute and chronic intestinal inflammation with many different clinical phenotypes. c INTRODUCTION The intestinal mucosa must rapidly recognise detrimental pathogenic threats to the lumen to initiate controlled immune responses but maintain hyporesponsiveness to omnipresent harmless commensals. Charles Janeway Jr first suggested that so-called pattern recognition receptors (PRRs) may play an essential role in allowing innate immune cells to discriminate between ‘‘self’’ http://gut.bmj.com/ and microbial ‘‘non-self’’ based on the recognition of broadly conserved molecular patterns.1 Toll- like receptors (TLRs) which comprise a class of transmembrane PRRs play a key role in microbial recognition, induction of antimicrobial genes, and the control of adaptive immune responses. NODs (NOD1 and NOD2) are a structurally distinct family of intracellular PRRs which presumably in the context of microbial invasion subserve similar functions (fig 1). -
An Immunologist's Perspective on Nutrition, Immunity, and Infectious
© 2009 Poultry Science Association, Inc. An immunologist’s perspective on nutrition, immunity, and infectious diseases: 1 Introduction and overview M. H. Kogut *2 and K. Klasing † * Southern Plains Agricultural Research Center, USDA-ARS, College Station, TX 77845; and † Department of Avian Sciences, University of California, Davis 95616 Primary Audience: Poultry Nutritionists, Immunologists, Veterinarians, Researchers SUMMARY The immune system is a multifaceted arrangement of membranes (skin, epithelial, and mucus), cells, and molecules whose function is to eradicate invading pathogens or cancer cells from a host. Working together, the various components of the immune system perform a balancing act of being lethal enough to kill pathogens or cancer cells yet specific so as not to cause extensive damage to “self” tissues of the host. A functional immune system is a requirement of a healthy life in modern animal production. Yet infectious diseases still represent a serious drain on the economics (reduced production, cost of therapeutics, and vaccines) and welfare of animal agriculture. The interaction involving nutrition and immunity and how the host deals with infectious agents is a strategic deter- minant in animal health. Almost all nutrients in the diet play a fundamental role in sustaining an op- timal immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Dietary components can regulate physiological functions of the body; interacting with the immune response is one of the most im- portant functions of nutrients. The pertinent question to be asked and answered in the current era of poultry production is whether the level of nutrients that maximizes production in commercial diets is sufficient to maintain competence of immune status and disease resistance. -
TLR Signaling Pathways
Seminars in Immunology 16 (2004) 3–9 TLR signaling pathways Kiyoshi Takeda, Shizuo Akira∗ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Abstract Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing spe- cific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling. © 2003 Elsevier Ltd. All rights reserved. Keywords: TLR; Innate immunity; Signal transduction; TIR domain 1. Introduction 2. Toll-like receptors Toll receptor was originally identified in Drosophila as an A mammalian homologue of Drosophila Toll receptor essential receptor for the establishment of the dorso-ventral (now termed TLR4) was shown to induce the expression pattern in developing embryos [1]. In 1996, Hoffmann and of genes involved in inflammatory responses [3]. In addi- colleagues demonstrated that Toll-mutant flies were highly tion, a mutation in the Tlr4 gene was identified in mouse susceptible to fungal infection [2]. This study made us strains that were hyporesponsive to lipopolysaccharide [4]. aware that the immune system, particularly the innate im- Since then, Toll receptors in mammals have been a major mune system, has a skilful means of detecting invasion by focus in the immunology field. -
Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes
University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2017-09-12 Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes Sreya Ghosh University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Immunity Commons, Immunology of Infectious Disease Commons, and the Microbiology Commons Repository Citation Ghosh S. (2017). Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes. GSBS Dissertations and Theses. https://doi.org/10.13028/M2CD6Z. Retrieved from https://escholarship.umassmed.edu/ gsbs_diss/928 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes A Dissertation Presented By Sreya Ghosh Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY September 12, 2017 Immunology and Microbiology Program Different Journeys, Same Destination: Exploring the Role of a PYHIN Protein and Involvement of Caspase-8 in the Regulation and Activation of Inflammasomes A Dissertation Presented By Sreya Ghosh The signatures of the Dissertation Defense Committee signify Completion and approval as to style and content of the Dissertation ____________________________________________ Katherine A. -
Innate Immunity and Inflammation of the Bovine Female Reproductive Tract
REPRODUCTIONREVIEW Innate immunity and inflammation of the bovine female reproductive tract in health and disease I Martin Sheldon, James G Cronin, Gareth D Healey, Christoph Gabler1, Wolfgang Heuwieser2, Dominik Streyl3, John J Bromfield4, Akio Miyamoto5, Chrys Fergani6 and Hilary Dobson6 College of Medicine, Institute of Life Science, Swansea University, Singleton Park, Swansea SA2 8PP, UK, 1Institute of Veterinary Biochemistry and 2Clinic of Animal Reproduction, Freie Universitaet Berlin, Berlin, Germany, 3Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, Ludwig Maximilian University of Munich, Oberschleißheim, Germany, 4Department of Animal Sciences, University of Florida, Gainesville, Florida 32608, USA, 5Graduate School for Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan and 6School of Veterinary Science, University of Liverpool, Leahurst, Neston CH64 7TE, UK Correspondence should be addressed to I M Sheldon; Email: [email protected] Abstract Mammalian reproductive physiology and the development of viviparity co-evolved with inflammation and immunity over millennia. Many inflammatory mediators contribute to paracrine and endocrine signalling, and the maintenance of tissue homeostasis in the female reproductive tract. However, inflammation is also a feature of microbial infections of the reproductive tract. Bacteria and viruses commonly cause endometritis, perturb ovarian follicle development and suppress the endocrine activity of the hypothalamus and pituitary in cattle. Innate immunity is an evolutionary ancient system that orchestrates host cell inflammatory responses aimed at eliminating pathogens and repairing damaged tissue. Pattern recognition receptors on host cells bind pathogen-associated molecular patterns and damage-associated molecular patterns, leading to the activation of intracellular MAPK and NFkB signalling pathways and the release of inflammatory mediators. -
Activation of Toll-Like Receptor 5 on Breast Cancer Cells by Flagellin Suppresses Cell Proliferation and Tumor Growth
Published OnlineFirst March 22, 2011; DOI: 10.1158/0008-5472.CAN-10-1993 Cancer Microenvironment and Immunology Research Activation of Toll-like Receptor 5 on Breast Cancer Cells by Flagellin Suppresses Cell Proliferation and Tumor Growth Zhenyu Cai, Amir Sanchez, Zhongcheng Shi, Tingting Zhang, Mingyao Liu, and Dekai Zhang Abstract Increasing evidence showed that Toll-like receptors (TLR), key receptors in innate immunity, play a role in cancer progression and development but activation of different TLRs might exhibit the exact opposite outcome, antitumor or protumor effects. TLR function has been extensively studied in innate immune cells, so we investigated the role of TLR signaling in breast cancer epithelial cells. We found that TLR5 was highly expressed in breast carcinomas and that TLR5 signaling pathway is overly responsive in breast cancer cells. Interestingly, flagellin/TLR5 signaling in breast cancer cells inhibits cell proliferation and an anchorage-independent growth, a hallmark of tumorigenic transformation. In addition, the secretion of soluble factors induced by flagellin contributed to the growth-inhibitory activity in an autocrine fashion. The inhibitory activity was further confirmed in mouse xenografts of human breast cancer cells. These findings indicate that TLR5 activation by flagellin mediates innate immune response to elicit potent antitumor activity in breast cancer cells themselves, which may serve as a novel therapeutic target for human breast cancer therapy. Cancer Res; 71(7); 1–10. Ó2011 AACR. Introduction (16, 17). Thus, the function and biological importance of TLRs expressed on various tumor cells seem complex. Toll-like receptors (TLR) are membrane-bound receptors Unlike other TLR family members, TLR5 is not expressed on that play key roles in both the innate and adaptive immune mouse macrophages and conventional dendritic cells (DC). -
Sex and Suicide: the Curious Case of Toll-Like Receptors
University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications in the Biological Sciences Papers in the Biological Sciences 3-23-2020 Sex and suicide: The curious case of Toll-like receptors Paulo A. Navarro-Costa Instituto Gulbenkian de Ciência & Universidade de Lisboa, [email protected] Antoine Molaro Fred Hutchinson Cancer Research Center Chandra S. Misra Instituto Gulbenkian de Ciência & Instituto de Tecnologia Quımica e Biologica Colin D. Meiklejohn University of Nebraska-Lincoln, [email protected] Peter J. Ellis University of Kent, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/bioscifacpub Part of the Biology Commons Navarro-Costa, Paulo A.; Molaro, Antoine; Misra, Chandra S.; Meiklejohn, Colin D.; and Ellis, Peter J., "Sex and suicide: The curious case of Toll-like receptors" (2020). Faculty Publications in the Biological Sciences. 772. https://digitalcommons.unl.edu/bioscifacpub/772 This Article is brought to you for free and open access by the Papers in the Biological Sciences at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications in the Biological Sciences by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. PLOS BIOLOGY UNSOLVED MYSTERY Sex and suicide: The curious case of Toll-like receptors 1,2 3 1,4 Paulo A. Navarro-CostaID , Antoine MolaroID , Chandra S. MisraID , Colin 5 6 D. MeiklejohnID , Peter J. EllisID * 1 Instituto Gulbenkian de Ciência, Oeiras,