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      A Functional Polymorphism in the Promoter Region of TLR3 Is Associated with Susceptibility to End-Stage Renal Disease

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          Abstract

          Background/Aims: End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD. Methods: We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells. Results: Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment. Conclusion: Results indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3.

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          Most cited references 28

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          TOLL-like receptors linking innate and adaptive immune response.

          Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognises pathogens by rearranged high affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors (PRR). Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns (PAMP) to TLR induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this review, we will summarize the discovery and the critical roles of the TLR family in host defense, briefly allude to signaling mechanisms mediating the response to TLR ligands, and will provide an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.
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            Of mice and men: species variations of Toll-like receptor expression.

             Michael Rehli (2002)
            Toll-like receptors (TLRs) comprise a family of evolutionary conserved pattern recognition molecules that have an essential role in mammalian innate immune defense. Recent observations suggest that several TLR orthologues are expressed differently in mice and humans - variations among both species include the expression of TLR transcripts in different cell types and different transcription regulation on cellular activation. Apparently some TLR genes have been placed into a completely different regulatory context during evolution. It will be interesting and important to clarify whether the observed regulatory differences influence innate immune responses in a species-specific manner.
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              An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population.

              The prevalence of atopic diseases has been increasing in developed countries. This could be explained by the hygiene hypothesis, which states that exposure to specific infections or endotoxins during infancy drives the maturing immune system towards a Th1 phenotype and away from the Th2 phenotype, which is associated with allergic diseases. Toll-like receptors (TLRs) play important roles in the signalling of many pathogen-related molecules and endogenous proteins associated with immune activation. The aim of the present study was to investigate whether polymorphisms in genes encoding TLRs are associated with asthma or total serum IgE levels. We screened the 5' flanking and coding regions of the TLR2,TLR3, TLR4, and TLR9 genes for polymorphisms by direct sequencing of DNA from 32 asthmatics, and analysed the effect of the polymorphisms on the development of atopic asthma and on total serum IgE levels. We identified 16 variants in TLRs. The transmission disequilibrium test of the families revealed that none of the alleles or haplotypes were associated with asthma or total IgE levels (P>0.05). However, we found an insertion/deletion polymorphism in the 5' untranslated region of TLR2, and an expression construct containing the deletion allele showed lower luciferase activity than the wild-type alleles, suggesting that the deletion allele has reduced transcriptional activity. Our results indicate that polymorphisms in TLRs are not likely to be associated with the development of atopy-related phenotypes in a Japanese population.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2014
                September 2014
                23 August 2014
                : 40
                : 2
                : 131-139
                Affiliations
                aSchool of Public Health, bDepartment of Biochemistry, National Defense Medical Center, cDivision of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, dDepartment of Aviation Medicine and Physical examination, National Defense Medical Center Tri-Service General Hospital Songshan Branch, eGraduate Institute of Life Sciences, National Defense Medical Center, Taipei, fDivision of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, and gDivision of Nephrology, Department of Medicine, Shuang Ho Hospital, Graduate Institute of Clinical Medicine, Taipei Medical University, New Taipei City, Taiwan
                Author notes
                *Dr. Sui-Lung Su, School of Public Health, National Defense Medical Center, No.161, Min-Chun E. Rd., Sec. 6, Neihu, Taipei 114 (Taiwan), E-Mail a131419@gmail.com
                Article
                365934 Am J Nephrol 2014;40:131-139
                10.1159/000365934
                25171218
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 5, Pages: 9
                Categories
                Original Report: Patient-Oriented, Translational Research

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