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Hichami A, Saidi H, Khan AS, Degbeni P, Khan NA. In Vitro Functional Characterization of Type-I Taste Bud Cells as Monocytes/Macrophages-like Which Secrete Proinflammatory Cytokines. Int J Mol Sci 2023; 24:10325. [PMID: 37373472 DOI: 10.3390/ijms241210325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/14/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
The sense of taste determines the choice of nutrients and food intake and, consequently, influences feeding behaviors. The taste papillae are primarily composed of three types of taste bud cells (TBC), i.e., type I, type II, and type III. The type I TBC, expressing GLAST (glutamate--aspartate transporter), have been termed as glial-like cells. We hypothesized that these cells could play a role in taste bud immunity as glial cells do in the brain. We purified type I TBC, expressing F4/80, a specific marker of macrophages, from mouse fungiform taste papillae. The purified cells also express CD11b, CD11c, and CD64, generally expressed by glial cells and macrophages. We further assessed whether mouse type I TBC can be polarized toward M1 or M2 macrophages in inflammatory states like lipopolysaccharide (LPS)-triggered inflammation or obesity, known to be associated with low-grade inflammation. Indeed, LPS-treatment and obesity state increased TNFα, IL-1β, and IL-6 expression, both at mRNA and protein levels, in type I TBC. Conversely, purified type I TBC treated with IL-4 showed a significant increase in arginase 1 and IL-4. These findings provide evidence that type I gustatory cells share many features with macrophages and may be involved in oral inflammation.
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Affiliation(s)
- Aziz Hichami
- Physiologie de la Nutrition & Toxicologie, UMR INSERM U1231 Lipide, Nutrition & Cancer, Université de Bourgogne, 21000 Dijon, France
| | - Hamza Saidi
- Physiologie de la Nutrition & Toxicologie, UMR INSERM U1231 Lipide, Nutrition & Cancer, Université de Bourgogne, 21000 Dijon, France
- Bioenergetics and Intermediary Metabolism Team, Laboratory of Biology and Organisms Physiology, University of Sciences and Technology Houari Boumediene, Algiers 16111, Algeria
| | - Amira Sayed Khan
- Physiologie de la Nutrition & Toxicologie, UMR INSERM U1231 Lipide, Nutrition & Cancer, Université de Bourgogne, 21000 Dijon, France
| | - Pernelle Degbeni
- Physiologie de la Nutrition & Toxicologie, UMR INSERM U1231 Lipide, Nutrition & Cancer, Université de Bourgogne, 21000 Dijon, France
| | - Naim Akhtar Khan
- Physiologie de la Nutrition & Toxicologie, UMR INSERM U1231 Lipide, Nutrition & Cancer, Université de Bourgogne, 21000 Dijon, France
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Chauhan A, Pandey N, Jain N. A review of methods for detecting single-nucleotide polymorphisms in the Toll-like receptor gene family. Biomark Med 2021; 15:1187-1198. [PMID: 34402632 DOI: 10.2217/bmm-2021-0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The Toll-like receptors play an essential role in immunity through targeting the pathogen-associated molecular patterns. Nucleotide variations in TLR genes, especially single-nucleotide polymorphisms, have been shown to alter host immune susceptibility to several infections and diseases. Since TLR genes' polymorphisms can be a promising biomarker, ongoing investigations aim to develop, optimize and validate SNP detection methods. This review discusses various TLR SNP detection methods, either used extensively or occasionally, but having a vast potential in high-throughput settings. Methods such as PCR-restriction fragment length polymorphism, TaqMan® assay, direct sequencing and matrix-assisted laser desorption ionization - time of flight mass spectroscopy MS are frequently used methods whereas Illumina GoldenGate® assay, reverse hybridization technology, PCR-confronting two-pair primers, KBiosciences KASPar® SNP assay, SNP stream®, PCR-fluorescence hybridization and SNaPshot® are powerful but sporadically used methods. We suggest that, for individual laboratories, the detection method of choice depends on a combination of factors such as throughput volume, reproducibility, feasibility and cost-effectiveness.
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Affiliation(s)
- Alex Chauhan
- P D Patel Institute of Applied Sciences, Charotar University of Science & Technology (CHARUSAT), Changa, 388421, India.,Norgen Biotek Corp., Ontario, L2V 4Y6, Canada
| | - Nilesh Pandey
- P D Patel Institute of Applied Sciences, Charotar University of Science & Technology (CHARUSAT), Changa, 388421, India.,Charotar Institute of Paramedical Sciences, Charotar University of Science & Technology (CHARUSAT), Changa, 388421, India
| | - Neeraj Jain
- P D Patel Institute of Applied Sciences, Charotar University of Science & Technology (CHARUSAT), Changa, 388421, India
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Ma PY, Tan JE, Hee EW, Yong DWX, Heng YS, Low WX, Wu XH, Cletus C, Kumar Chellappan D, Aung K, Yong CY, Liew YK. Human Genetic Variation Influences Enteric Fever Progression. Cells 2021; 10:cells10020345. [PMID: 33562108 PMCID: PMC7915608 DOI: 10.3390/cells10020345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 01/06/2023] Open
Abstract
In the 21st century, enteric fever is still causing a significant number of mortalities, especially in high-risk regions of the world. Genetic studies involving the genome and transcriptome have revealed a broad set of candidate genetic polymorphisms associated with susceptibility to and the severity of enteric fever. This review attempted to explain and discuss the past and the most recent findings on human genetic variants affecting the progression of Salmonella typhoidal species infection, particularly toll-like receptor (TLR) 4, TLR5, interleukin (IL-) 4, natural resistance-associated macrophage protein 1 (NRAMP1), VAC14, PARK2/PACRG, cystic fibrosis transmembrane conductance regulator (CFTR), major-histocompatibility-complex (MHC) class II and class III. These polymorphisms on disease susceptibility or progression in patients could be related to multiple mechanisms in eliminating both intracellular and extracellular Salmonella typhoidal species. Here, we also highlighted the limitations in the studies reported, which led to inconclusive results in association studies. Nevertheless, the knowledge obtained through this review may shed some light on the development of risk prediction tools, novel therapies as well as strategies towards developing a personalised typhoid vaccine.
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Affiliation(s)
- Pei Yee Ma
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Jing En Tan
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Edd Wyn Hee
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dylan Wang Xi Yong
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Yi Shuan Heng
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Wei Xiang Low
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Xun Hui Wu
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Christy Cletus
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Kyan Aung
- Department of Pathology, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Chean Yeah Yong
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia;
| | - Yun Khoon Liew
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
- Correspondence:
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Juyal G, Sood A, Midha V, Thelma BK. Genetics of ulcerative colitis: putting into perspective the incremental gains from Indian studies. J Genet 2018; 97:1493-1507. [PMID: 30555100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Ulcerative colitis (UC), one of the two clinical subtypes of inflammatory bowel disease is perceived as a potential 'sleeping giant' in the Indian subcontinent. Clinical manifestation is overall believed to be the same across ethnic groups but overwhelming genetics from large European and fewer non-European studies have revealed shared as well as unique disease susceptibly signaturesbetween them, pointing to population specific differences at genomic and environmental levels. A systematic recount of the four major eras in UC genetics spanning earliest linkage analysis, cherry picked candidate gene association studies, unbiased genomewide association studies, their logical extension in trans-ethnic setting (Immunochip study), lastly whole exome sequencing efforts forrare variant burden; and lessons learnt thereof in context of genetically distinct Indian population was attempted in this review. Genetic heterogeneity manifesting at allelic/locus level across these approaches has been the consistent finding through the range of pan India studies. On the other hand, these salient findings also highlight the limitations of even the best of these genetic leadsfor prognostic/clinical application. The imminent need, therefore, for the UC research community to adopt newer approaches/tools with improved study design to (i) gain better insight into genetic/mechanistic basis of disease; (ii) identify biomarkers of immediate translational value; and (iii) develop new/alternate therapeutic options is emphasized at the end.
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Affiliation(s)
- Garima Juyal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110 067, India. ,
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Genetics of ulcerative colitis: putting into perspective the incremental gains from Indian studies. J Genet 2018. [DOI: 10.1007/s12041-018-1015-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Huang C, Zhang H, Bai R, Wang L, Lv J. A896G and C1196T Polymorphisms Within the TLR4 Gene Abate Toll-Like Receptor 4-Mediated Signaling in HepG2 Cells. DNA Cell Biol 2017; 36:1029-1038. [PMID: 28945461 DOI: 10.1089/dna.2017.3892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Toll-like receptor 4 (TLR4) appears to play an important role in the development and progression of hepatocellular carcinoma (HCC), but it is unclear whether single-nucleotide polymorphisms (SNPs) in the TLR4 gene influence HCC. In this study, we investigated the effects of TLR4 SNPs on HepG2 cell survival and proliferation, migration, and invasion. Plasmids carrying wild-type or mutant versions of the TLR4 gene (A896G and/or C1196T) were stably transfected into HepG2 cells, and cell viability and proliferation were analyzed using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, whereas apoptosis was assessed using flow cytometry. Migration and invasion were measured in a transwell chamber assay, and expression of inflammatory cytokines and downstream effectors was examined using real-time PCR and western blotting. Specific inhibitors of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), or phosphatidylinositol 3-kinase (PI3K) were added to the HepG2 cultures to explore the potential role of each pathway in TLR4 signaling. TLR4 SNPs did not affect expression levels in transfected cells. Compared with wild-type TLR4, mutant TLR4 was associated with lower cell proliferation, migration, invasion, and apoptotic threshold. In addition, the mutations were associated with significantly lower expression of nuclear factor κB (NF-κB), IL-6, and TGF-β1, even after stimulation with lipopolysaccharide. The expression of p-Akt was similar in the presence of wild-type or mutant TLR4. The 896G and 1196T SNPs in the TLR4 gene are associated with reduced TLR4-mediated signaling and, therefore, with lower survival, proliferation, and metastasis in HepG2 cells.
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Affiliation(s)
- Cuiyuan Huang
- Department of Pharmacy, Renmin Hospital of Wuhan University , Wuhan, China
| | - Hong Zhang
- Department of Pharmacy, Renmin Hospital of Wuhan University , Wuhan, China
| | - Ruidan Bai
- Department of Pharmacy, Renmin Hospital of Wuhan University , Wuhan, China
| | - Li Wang
- Department of Pharmacy, Renmin Hospital of Wuhan University , Wuhan, China
| | - Jian Lv
- Department of Pharmacy, Renmin Hospital of Wuhan University , Wuhan, China
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Zhang J, Yang J, Xu X, Liang L, Sun H, Liu G, Zhang L, Su Y. The influence of genetic polymorphisms in TLR4 and TIRAP, and their expression levels in peripheral blood, on susceptibility to sepsis. Exp Ther Med 2015; 11:131-139. [PMID: 26889229 PMCID: PMC4726872 DOI: 10.3892/etm.2015.2884] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 10/06/2015] [Indexed: 12/28/2022] Open
Abstract
The present study aimed to investigate whether genetic polymorphisms in the Toll-like receptor (TLR)-4 and Toll/interleukin-1 receptor (TIR)-associated protein (TIRAP) genes, and/or their expression levels, influence the susceptibility of a patient to sepsis. A total of 106 patients with sepsis were divided into two groups on the basis of their acute physiology and chronic health evaluation (APACHE) II scores: i) Sepsis group A (APACHE II <20) and ii) Sepsis group B (APACHE II >20). In addition, 100 healthy volunteers were enrolled into the control group. Polymerase chain reaction-restriction fragment length polymorphism assay was used to detect the following genetic polymorphisms: The Ser180Leu allele of the TIRAP gene and the Asp299Gly and Thr399I1e alleles of the TLR4 gene. Furthermore, the protein expression levels of TLR4 and TIRAP were analyzed using an enzyme-linked immunosorbent assay. Genetic polymorphisms were not detected for the TLR4 and TIRAP genes; however, the protein expression levels of TLR4 and TIRAP differed significantly between the control, sepsis A and sepsis B groups (P<0.01). An APACHE II score of 20 was used as a baseline in order to differentiate sepsis severity. Pearson analysis demonstrated that TLR4 and TIRAP protein expression levels were positively correlated with sepsis severity (r=0.931 and 0.972; P<0.05), and TLR4 protein expression levels were positively correlated with those of TIRAP (r=0.936; P<0.05). The results of the present study suggested that the protein expression levels of, but not genetic polymorphisms in, TLR4 and TIRAP were associated with the severity of sepsis.
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Affiliation(s)
- Jianping Zhang
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Jingping Yang
- Department of Respiratory and Critical Medicine, The Third Affiliated Hospital of Inner Mongolia Medical University, Baotou, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Xiyuan Xu
- Department of Respiratory and Critical Medicine, The Third Affiliated Hospital of Inner Mongolia Medical University, Baotou, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Liangshen Liang
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Haixia Sun
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Guohua Liu
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Lihong Zhang
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
| | - Yun Su
- Department of Critical Medicine, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 014010, P.R. China
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Cheng Y, Zhu Y, Huang X, Zhang W, Han Z, Liu S. Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. PLoS One 2015; 10:e0126803. [PMID: 26023918 PMCID: PMC4449210 DOI: 10.1371/journal.pone.0126803] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 04/08/2015] [Indexed: 12/18/2022] Open
Abstract
Background The associations between toll-like receptor 2 (TLR2) and toll-like receptor 4(TLR4) polymorphisms and inflammatory bowel disease (IBD) susceptibility remain controversial. A meta-analysis was performed to assess these associations. Methods A systematic search was performed to identify all relevant studies relating TLR2 and TLR4 polymorphisms and IBD susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by ethnicity and publication quality. Results Thirty-eight eligible studies, assessing 10970 cases and 7061 controls were included. No TLR2 Arg677Trp polymorphism was found. No significant association was observed between TLR2 Arg753Gln polymorphism and Crohn’s disease (CD) or ulcerative colitis (UC) in all genetic models. Interestingly, TLR4 Asp299Gly polymorphism was significantly associated with increased risk of CD and UC in all genetic models, except for the additive one in CD. In addition, a statistically significant association between TLR4 Asp299Gly polymorphism and IBD was observed among high quality studies evaluating Caucasians, but not Asians. Associations between TLR4 Thr399Ile polymorphisms and CD risk were found only in the allele and dominant models. The TLR4 Thr399Ile polymorphism was associated with UC risk in pooled results as well as subgroup analysis of high quality publications assessing Caucasians, in allele and dominant models. Conclusions The meta-analysis provides evidence that TLR2 Arg753Gln is not associated with CD and UC susceptibility in Asians; TLR4 Asp299Gly is associated with CD and UC susceptibility in Caucasians, but not Asians. TLR4 Thr399Ile may be associated with IBD susceptibility in Caucasians only. Additional well-powered studies of Asp299Gly and other TLR4 variants are warranted.
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Affiliation(s)
- Yang Cheng
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Yun Zhu
- Liver Tumor Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xiuping Huang
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Wei Zhang
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zelong Han
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Side Liu
- Department of Digestion, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
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Senhaji N, Diakité B, Serbati N, Zaid Y, Badre W, Nadifi S. Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: New data and a meta-analysis. BMC Gastroenterol 2014; 14:206. [PMID: 25492126 PMCID: PMC4279599 DOI: 10.1186/s12876-014-0206-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Accepted: 11/24/2014] [Indexed: 01/21/2023] Open
Abstract
Background The pathogenesis of inflammatory bowel disease (IBD) involves interactions between the host genetic susceptibility, intestinal microflora and mucosal immune responses through the pattern recognition receptor. Polymorphisms in toll-like receptor 4 (TLR4) induce an aberrant immune response to indigenous intestinal flora, which might favor IBD development. In this study, we aimed to determine whether TLR4 gene was associated with Crohn’s disease (CD) and ulcerative colitis (UC) among Moroccan patients, and evaluated its correlation with clinical manifestation of the disease. Methods The study population comprised 117 patients with IBD and 112 healthy unrelated blood donors. TLR4 polymorphisms: Asp299Gly and Thr399Ile were genotyped by polymerase chain reaction-restriction fragment length polymorphism. PCR products were cleaved with Nco I for the Asp299Gly polymorphism and Hinf I for the Thr399Ile polymorphism. Meta-analysis was performed to test the association of 299Gly and 399Ileu carriage with CD, UC and the overall IBD risk. Results Our study revealed that the frequency of Asp299Gly and Thr399Ile did not differ significantly between patients and controls in the Moroccan population. However, meta-analysis demonstrated significantly higher frequencies of both Asp299Gly and Thr399Ile SNPs in IBD and CD and for 399Ileu carriage in UC patients. Conclusion The meta-analysis provides evidence that TLR4 polymorphisms confer a significant increased risk for the overall IBD development.
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Affiliation(s)
- Nezha Senhaji
- Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco.
| | - Brehima Diakité
- Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco.
| | - Nadia Serbati
- Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco.
| | - Younes Zaid
- Laboratory of Thrombosis and Haemostasis Research Centre, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.
| | - Wafaa Badre
- Gastroenterology Department, CHU Ibn Rochd, Casablanca, Morocco.
| | - Sellama Nadifi
- Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco.
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Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol 2014; 5:304-21. [PMID: 25133031 PMCID: PMC4133528 DOI: 10.4291/wjgp.v5.i3.304] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/19/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.
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Rodriguez-Osorio CA, Lima G, Herrera-Caceres JO, Villegas-Torres BE, Zuñiga J, Ponce-de-Leon S, Llorente L, Sifuentes-Osornio J. Genetic variations in toll-like receptor 4 in Mexican-Mestizo patients with intra-abdominal infection and/or pneumonia. Immunol Lett 2013; 153:41-6. [DOI: 10.1016/j.imlet.2013.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 06/07/2013] [Accepted: 07/08/2013] [Indexed: 12/29/2022]
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Polymorphisms of Toll-like receptor-4 and CD14 in systemic lupus erythematosus and rheumatoid arthritis. Biomark Res 2013; 1:20. [PMID: 24252506 PMCID: PMC4177616 DOI: 10.1186/2050-7771-1-20] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 05/08/2013] [Indexed: 01/23/2023] Open
Abstract
Background Toll-like receptor 4 (TLR4) and its co-receptor CD14 play a major role in innate immunity by recognizing PAMPs and signal the activation of adaptive responses. These receptors can recognize endogenous ligands mainly auto-antigens. In addition, TLR4 (Asp299Gly) and CD14 (C/T -159) polymorphisms (SNPs) may modify qualitatively and/or quantitatively their expression. Therefore, they could be implied in autoimmune diseases and can influence both susceptibility and severity of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Patients and methods TLR4 (Asp299Gly) and CD14 (C/T -159) SNPs were genotyped using polymerase chain reaction (PCR)-RFLP in 127 SLE patients, 100 RA patients, and 114 healthy controls matched in age and gender. Results CD14*T allele was significantly more frequent in SLE patients (0.456) comparatively to controls (0.355), p = 0.02 OR (95% CI) = 1.53 [1.04-2.24]. In RA patients, the higher frequency of CD14*T allele (0.405) failed to reach significance, p = 0.28. Investigation of the TLR4 (Asp299Gly) SNP showed no significant association neither with SLE nor with RA. Analysis of these SNPs according to clinical and biological features showed a significant higher frequency of arthritis in SLE patients carrying CD14*T/T genotype (92%) comparatively to those with C/C and C/T genotypes (72.5%), p = 0.04. Moreover, SLE patients carrying CD14*T/T/TLR4*A/A haplotype had significantly more arthritis (91.3%) than the rest of SLE group (73%), p = 0,044 and confirmed by multivariable analysis after adjustment according to age and gender, p = 0.01. Conclusion The CD14 (-159)*T allele seems to be associated with susceptibility to SLE and arthritis occurrence.
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TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2012; 10:165-75. [PMID: 23262974 DOI: 10.1038/cmi.2012.58] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4(-/-)) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4(-/-) mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4(+/+)) mice. In addition, histopathological analyses revealed that in TLR4(-/-)→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4(+/+), TLR4(-/-) mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4(-/-) mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4(+/+) mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4(-/-)→BALB/c than in TLR4(+/+)→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
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Chen L, Lin MJ, Zhan LL, Lv XP. Analysis of TLR4 and TLR2 polymorphisms in inflammatory bowel disease in a Guangxi Zhuang population. World J Gastroenterol 2012; 18:6856-6860. [PMID: 23239925 PMCID: PMC3520176 DOI: 10.3748/wjg.v18.i46.6856] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/18/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the polymorphisms of toll-like receptor 4 (TLR4) gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp and susceptibility to inflammatory bowel disease (IBD) in the Zhuang population from Guangxi, China.
METHODS: A case-control study was performed from February 2007 to October 2011 which included 146 Zhuang patients with IBD in the experimental group and 164 healthy Zhuang subjects who acted as the control group. All patients and healthy subjects were from the Guangxi Zhuang Autonomous Region of China. Genomic DNA was extracted from intestinal tissue by the phenol chloroform method. TLR4 gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp were amplified by polymerase chain reaction (PCR), and then detected by PCR-restriction fragment length polymorphism (RFLP).
RESULTS: The TLR4 gene Asp299Gly was digested using Nco I restriction enzyme, and a single band of 249 bp was observed which showed that it was a wild type (AA). The TLR4 gene Thr399Ile was digested using Hinf Irestriction enzyme and only the wild type (CC) was detected. In addition, the TLR2 gene Arg677Trp was digested using Aci I restriction enzyme and only the wild type (CC) was detected. The TLR2 gene Arg753Gln was digested using Pst I restriction enzyme. Only the wild type (GG) as a single band of 254 bp was observed during RFLP. Overall, no heterozygous or homozygous single nucleotide polymorphism mutations were found in patients with Crohn’s disease and ulcerative colitis both in the TLR4 gene Asp299Gly, Thr399Ile and the TLR2 gene Arg677Trp, Arg753Gln in the Zhuang population from the Guangxi Zhuang Autonomous Region of China.
CONCLUSION: The TLR4 gene Asp299Gly, Thr399Ile and TLR2 gene Arg753Gln, Arg677Trp polymorphisms may not be associated with IBD in the Zhuang population from the Guangxi Zhuang Autonomous Region of China.
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Rasouli M, Keshavarz M, Kalani M, Moravej A, Kiany S, Badiee P. Toll-like receptor 4 (TLR4) polymorphisms in Iranian patients with visceral leishmaniasis. Mol Biol Rep 2012; 39:10795-802. [PMID: 23053976 DOI: 10.1007/s11033-012-1973-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 10/01/2012] [Indexed: 12/22/2022]
Abstract
The role of Toll-like receptor (TLR) 4 in visceral leishmaniasis (VL), a disease caused by an obligate intracellular protozoan parasites belonging to the genus Leishmania, has been shown in the recent leishmaniasis experimental studies. As genetic host factors play an important role in the susceptibility and/or resistance to VL, the association between TLR4 gene mutations [A896G and C1196T single nucleotide polymorphisms (SNPs)] and VL was investigated. Genotyping of A896G (Asp299Gly) and C1196T (Thr399Ile) SNPs was performed in the patients with VL (N = 122) and ethnically matched controls (N = 155) using polymerase chain reaction-restriction fragment length polymorphism method. When VL patients and the controls were compared, no statistically significant differences were observed in A896G and C1196T alleles and genotypes (P > 0.05). The TLR4 A896G and C1196T were in moderate linkage disequilibrium in the controls and patients (r (2) = 0.497, 0.548 and D' = 0.705, 0.808, respectively), and haplotypes reconstructed from these SNPs were not significantly different between the aforementioned study groups. In conclusion, based on the results, TLR4 gene polymorphisms at the positions 896 and 1196 cannot be regarded as the major contributors to VL susceptibility among the Iranian population.
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Affiliation(s)
- Manoochehr Rasouli
- Department of Immunology, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, 71937-11351, Shiraz, Iran.
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Reddy BH, Jayakumar ND, Akula SR, Sharma R, Kaarthikeyan G, Sankari. Analysis of association between TLR-4 Asp299Gly and Thr399Ile gene polymorphisms and chronic periodontitis in a sample of south Indian population. J Indian Soc Periodontol 2012; 15:366-70. [PMID: 22368361 PMCID: PMC3283934 DOI: 10.4103/0972-124x.92571] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 04/08/2011] [Indexed: 12/02/2022] Open
Abstract
Background: To analyze the association between TLR-4 Asp299Gly and Thr399Ile gene polymorphisms and chronic periodontitis in a sample of south Indian population. Materials and Methods: Genomic DNA was obtained from peripheral blood of 60 patients with chronic periodontitis and 60 periodontally healthy subjects. TLR-4 Asp299Gly and Thr399Ile gene polymorphisms were genotyped by a polymerase chain reaction–restriction fragment length polymorphism method. The data were analyzed by a χ2-test and by relative risk estimation. Results: Thr399Ile alleles were found in 4% of chronic periodontitis patients and in 1% of periodontally healthy subjects. The prevalence of a Thr399Ile heterozygote was found to be 5% in the chronic periodontitis group and 1.67% in the periodontally healthy group, respectively. Homozygosity for TLR-4 Thr399Ile was seen in chronic periodontitis patients only, which was 1.67%. The TLR-4 Asp299Gly gene polymorphism was not detected in either chronic periodontitis or periodontally healthy groups. Conclusion: There is no significant association between TLR-4 Thr399Ile polymorphism and chronic periodontitis in a sample of south Indian population.
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Affiliation(s)
- Bavigadda Harish Reddy
- Department of Periodontics, SVS Institute of Dental Sciences, Appannapally, Mahabubnagar, Andhra Pradesh, India
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Voronko OE, Dmitrieva-Zdorova EV, Latysheva EA, Aksenova MG, Storozhakov GI, Bodoev NV, Archakov AI. CARD15 and TLR4 polymorphisms in atopic bronchial asthma. Mol Biol 2011. [DOI: 10.1134/s0026893311040121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Bhuvanendran S, Hussin HM, Meran LP, Anthony AA, Zhang L, Burch LH, Phua KK, Ismail A, Balaram P. Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and typhoid susceptibility in Asian Malay population in Malaysia. Microbes Infect 2011; 13:844-51. [PMID: 21612766 DOI: 10.1016/j.micinf.2011.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 04/10/2011] [Accepted: 04/18/2011] [Indexed: 12/19/2022]
Abstract
Typhoid fever is a major health problem with frequent outbreaks in Kelantan, Malaysia. Prevalence of TLR4 gene polymorphisms varies with ethnic groups (0-20%) and predisposean individual to gram-negative infections. The prevalence rate of TLR4 Asp299Gly and Thr399lle polymorphisms in the Malay population or the influence of these on typhoid fever susceptibility is not yet reported. 250 normal and 304 susceptible Malay individuals were investigated for these polymorphisms using allele-specific PCR and analysed for its association with typhoid fever susceptibility. The total prevalence of polymorphisms in the normal population was 4.8% in comparison to 12.5% in the susceptible population (p = 0.002). An increased frequency of both polymorphisms was observed in the susceptible population (p < 0.01) with no homozygous mutants observed. Co-segregation was observed in 2% of controls and 3.6% of the susceptible individuals. This study, for the first time, reports the prevalence of TLR4 gene polymorphisms in the Malay population and suggests that these polymorphisms confer a higher risk for typhoid, infection. The higher incidence of typhoid fever in Kelantan could be attributed to the higher percentage of Malays (95%) in this state. In order to reduce the incidence of this disease, people with these polymorphisms, can be prioritised for prophylactic strategies.
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Affiliation(s)
- Saatheeyavaane Bhuvanendran
- Institute for Research in Molecular Medicine, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
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Abstract
Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.
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Affiliation(s)
- Dianhua Jiang
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.
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21
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Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. FIBROGENESIS & TISSUE REPAIR 2010; 3:21. [PMID: 20964825 PMCID: PMC2984459 DOI: 10.1186/1755-1536-3-21] [Citation(s) in RCA: 238] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 10/21/2010] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.
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Affiliation(s)
- Jinsheng Guo
- Division of Liver Diseases, Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY, USA.
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22
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Najmi N, Kaur G, Sharma SK, Mehra NK. Human Toll-like receptor 4 polymorphisms TLR4 Asp299Gly and Thr399Ile influence susceptibility and severity of pulmonary tuberculosis in the Asian Indian population. ACTA ACUST UNITED AC 2010; 76:102-9. [PMID: 20403143 DOI: 10.1111/j.1399-0039.2010.01481.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Genetic polymorphisms in Toll-like receptor 4, TLR4 896 A/G (Asp299Gly) and 1196 C/T (Thr399Ile) have been reported to influence TLR4 function and the innate host immune response to mycobacteria. We investigated the effect of these single nucleotide polymorphisms on susceptibility and severity of pulmonary tuberculosis (PTB) in the Asian Indian population. A significantly increased frequency of TLR4 Asp299Gly mutation was observed in the patient group (17%) as compared with healthy controls [8.8%, chi(2) = 10.7, P = 0.001,odds ratio (OR ) = 2.1]. On the other hand, the TLR4 Thr399Ile mutation occurred with comparable frequencies in the two groups (12.6% among patients and 9% in healthy controls). The PTB patients were categorized on the basis of their bacillary load as 3+, 2+, 1+, negative and on the extent of lung involvement as having minimal, moderate, and far-advanced lung disease. The 299Gly mutant occurred in homozygous state (GG) only in patients with high bacillary load (3+) and those with far-advanced lung disease. Similarly, the mutant 399Ile was significantly pronounced in these patients in the homozygous state (TT). The present data suggest that TLR4 substitutions at residues 299 and 399 are associated with pulmonary TB, particularly, the most severe disease.
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Affiliation(s)
- N Najmi
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
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23
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Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int 2010; 30:1249-52. [PMID: 20306049 DOI: 10.1007/s00296-010-1400-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2009] [Accepted: 02/27/2010] [Indexed: 12/27/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovium and subsequent joint destruction. Recently, genetic polymorphisms within the toll-like receptor 4 (TLR4) genes have been reported to be associated with RA. To analyze the association between the genetic polymorphisms within TLR4 gene and the susceptibility to RA in Chinese people, two functional variants, Asp299Gly and Thr399Ile, in the TLR4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing techniques from 213 RA patients and 247 ethnically matched controls. None polymorphisms of Asp299Gly and Thr399Ile were detected in all RA cases and controls, which indicates that there is no relevance between these two SNPs and RA in the Chinese Han population. Further studies with extended single nucleotide polymorphisms (SNP) should be performed.
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Zheng B, Wei C, Shou T, Li Q, Yang M, Yi L, Zhou R, Shao J, Xiao C. A unique display of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in non-Han Chinese Hani population. Int J Immunogenet 2010; 37:43-6. [DOI: 10.1111/j.1744-313x.2009.00878.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Takagi Y, Masamune A, Kume K, Satoh A, Kikuta K, Watanabe T, Satoh K, Hirota M, Shimosegawa T. Microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene is associated with susceptibility to acute pancreatitis in Japan. Hum Immunol 2009; 70:200-4. [PMID: 19280717 DOI: 10.1016/j.humimm.2009.01.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This study evaluated the association of the polymorphisms in the Toll-like receptor (TLR)2 and TLR4 genes with acute pancreatitis (AP) in Japan. The numbers of guanine-thymine [(GT)n] repeats in intron 2 of the TLR2 gene were counted in 202 unrelated patients with AP (80 with severe and 122 with mild disease) and in 286 healthy controls, using polymerase chain reaction and Genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele; between (GT)17 and (GT)22 as the M allele; and (GT)23 or more as the L allele. Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene were examined by polymerase chain reaction-restriction fragment length polymorphism analysis. Patients with AP had more S alleles (p < 0.001; odds ratio = 2.37; 95% confidence interval = 1.78-3.17) and fewer M alleles (p < 0.001; odds ratio = 0.40; 95% confidence interval 0.31-0.52) than did healthy controls. Genotypes SS and SL were more common, whereas MM and ML were less common in patients with AP. In subgroup analyses, the genotypes including S alleles were more common in patients with severe AP than in controls. No Asp299Gly and Thr399Ile polymorphisms were detected. In conclusion, microsatellite polymorphism in intron 2 of the TLR2 gene was associated with susceptibility to AP and its severity in Japan.
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Affiliation(s)
- Yasuhiko Takagi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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26
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Zouiten-Mekki L, Kharrat M, Karoui S, Serghimi M, Fekih M, Matri S, Kallel L, Boubaker J, Filali A, Chaabouni H. Tolllike receptor 4 (TLR4) polymorphisms in Tunisian patients with Crohn's disease: genotype-phenotype correlation. BMC Gastroenterol 2009; 9:62. [PMID: 19664207 PMCID: PMC2736969 DOI: 10.1186/1471-230x-9-62] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 08/07/2009] [Indexed: 01/25/2023] Open
Abstract
Background The immune responses to bacterial products through the pattern recognition receptor (PRR) play a pivotal role in pathogenesis of Crohn's disease. A recent study described an association between CD and some gene coding for bacterial receptor like NOD2/CARD15 gene and TLR4. In this study, we sought to determine whether TLR4 gene was associated with Crohn's disease (CD) among the Tunisian population and its correlation with clinical manifestation of the disease. Methods 90 patients with CD and 80 healthy individuals are genotyped for the Asp299Gly and Thr399Ile polymorphisms by restriction fragment length polymorphism analysis. Results The allele and genotype frequency of the TLR4 polymorphisms did not differ between patients and controls. The genotype-phenotype correlation permitted to show that the Thr399Ile polymorphism was associated with early onset disease. Conclusion this study reported the absence of association between CD and TLR4 gene in the Tunisian population, but this gene could play a role in clinical expression of the disease.
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27
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Ye BD, Yang SK, Song K, Yang DH, Yoon SM, Kim KJ, Byeon JS, Myung SJ, Kim JH. Association of Toll-Like Receptor Gene with Crohn's Disease in Koreans. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2009; 54:377-83. [DOI: 10.4166/kjg.2009.54.6.377] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Byong Duk Ye
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Soon Man Yoon
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyung Jo Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung-Jae Myung
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jin-Ho Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Levin A, Shibolet O. Toll-like receptors in inflammatory bowel disease-stepping into uncharted territory. World J Gastroenterol 2008; 14:5149-53. [PMID: 18777591 PMCID: PMC2744004 DOI: 10.3748/wjg.14.5149] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease are chronic relapsing-remitting inflammatory processes of the intestinal tract. The etiology of these diseases is currently unknown. However, inflammation is hypothesized to result from inappropriate activation of mucosal immunity by luminal antigens in genetically susceptible individuals. Toll-like receptors (TLRs) are a family of transmembrane proteins that act as microbial pattern recognition receptors. They are crucial initiators of innate immune responses. The role of TLRs in the pathogenesis of inflammatory bowel disease (IBD) has not been fully elucidated. In this review, we aim to analyze the available data connecting individual TLRs to intestinal inflammation and IBD.
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Lanciotti M, Pigullo S, Lanza T, Dufour C, Caviglia I, Castagnola E. Possible role of toll-like receptor 9 polymorphism in chemotherapy-related invasive mold infections in children with hematological malignancies. Pediatr Blood Cancer 2008; 50:944. [PMID: 17894360 DOI: 10.1002/pbc.21367] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Fukusaki T, Ohara N, Hara Y, Yoshimura A, Yoshiura K. Evidence for association between a Toll-like receptor 4 gene polymorphism and moderate/severe periodontitis in the Japanese population. J Periodontal Res 2008; 42:541-5. [PMID: 17956467 DOI: 10.1111/j.1600-0765.2007.00979.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND OBJECTIVE Chronic periodontitis is an inflammatory disease caused by bacteria in subgingival pockets. Because Toll-like receptor 2 and Toll-like receptor 4 have been shown to play an important role in the recognition of periodontal pathogens, we investigated the relevance of genetic variations in TLR2 and TLR4 to susceptibility to periodontitis. MATERIAL AND METHODS A total of 97 patients with chronic periodontitis and 100 control subjects were examined for mutations in TLR2 and TLR4. Case-control analysis was performed using individual single nucleotide polymorphisms detected during the mutation search. RESULTS The missense mutations reported previously in TLR2 (677 Arg>Trp and 753 Arg>Gln) and in TLR4 (299 Asp>Gly and 399 Thr>Ile) were not detected in 97 of the Japanese patients with chronic periodontitis or in 100 of the Japanese control subjects. Nine single nucleotide polymorphisms were identified in exons of TLR2 and TLR4. The case-control analysis revealed that the frequency of the C/C genotype at base-pair position +3725 in TLR4 was significantly higher in both the moderate and the severe periodontitis patient group than in the control group. CONCLUSION A genetic variation of TLR4 might be associated with moderate and severe periodontitis in the Japanese population.
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Affiliation(s)
- T Fukusaki
- Department of Periodontology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Analysis of single nucleotide polymorphisms in Toll-like receptor 4 shows no association with ankylosing spondylitis in a Korean population. Rheumatol Int 2007; 28:627-30. [DOI: 10.1007/s00296-007-0490-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2007] [Accepted: 11/06/2007] [Indexed: 10/22/2022]
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32
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Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, Boukhvalova MS, Hemming VG, Blanco JCG, Vogel SN. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. THE JOURNAL OF IMMUNOLOGY 2007; 179:3171-7. [PMID: 17709532 DOI: 10.4049/jimmunol.179.5.3171] [Citation(s) in RCA: 147] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Although anti-RSV Ab prophylaxis has greatly reduced infant mortality in the United States, there is currently no vaccine or effective antiviral therapy. RSV fusion (F) protein activates cells through TLR4. Two single nucleotide polymorphisms (SNPs) encoding Asp299Gly and Thr399Ile substitutions in the TLR4 ectodomain were previously associated with TLR4 hyporesponsiveness and increased susceptibility to bacterial infection. Prevalence of these SNPs was analyzed in a case series of 105 DNA samples extracted from archived nasal lavage samples from high-risk infants/young children with confirmed RSV disease who participated in two seminal clinical trials for anti-RSV prophylaxis. Frequencies of TLR4 SNPs in the case series were compared with those of literature controls, healthy adults, infants, and young children who presented with symptoms of respiratory infections (but not preselected for high risk for RSV). Both SNPs were highly associated with symptomatic RSV disease in this largely premature population (p < 0.0001), with 89.5% and 87.6% of cases being heterozygous for Asp299Gly and Thr399Ile polymorphisms versus published control frequencies of 10.5% and 6.5%, respectively. The other two control groups had similarly low frequencies. Our data suggest that heterozygosity of these two extracellular TLR4 polymorphisms is highly associated with symptomatic RSV disease in high-risk infants and support a dual role for TLR4 SNPs in prematurity and increased susceptibility to RSV not revealed by analysis of either alone.
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Affiliation(s)
- Agnes A Awomoyi
- Department of Microbiology and Immunology, University of Maryland-Baltimore, 660 W. Redwood Street, Baltimore, MD 21201, USA
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Speletas M, Liadaki K, Kalala F, Daiou C, Katodritou E, Mandala E, Korantzis I, Ritis K, Zintzaras E, Germenis AE. TLR4 single nucleotide polymorphisms and thrombosis risk in patients with myeloproliferative disorders. Thromb Res 2007; 122:27-32. [PMID: 17999935 DOI: 10.1016/j.thromres.2007.09.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2007] [Revised: 09/20/2007] [Accepted: 09/21/2007] [Indexed: 11/28/2022]
Affiliation(s)
- M Speletas
- Department of Immunology and Histocompatibility, School of Medicine, University Hospital of Thessaly, Larissa, 41110 Larissa, Greece.
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Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J Gastroenterol Hepatol 2007; 22:1760-6. [PMID: 17914947 DOI: 10.1111/j.1440-1746.2006.04727.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Toll-like receptors (TLRs) have been identified as susceptibility genes for Crohn's disease (CD) in some, but not all, studies. Here we examined the association between candidate disease-susceptibility polymorphisms in the TLR2, TLR4 and TLR9 genes and CD in a New Zealand Caucasian population. METHODS The frequency of gene polymorphisms was examined in 182 CD patients and in 188 ethnically matched controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS We could not detect any significant difference in the allele frequencies of polymorphisms in the TLR2 (R753Q, 0.029 vs 0.016, P = 0.25), TLR4 (D299G and T399I, 0.085 vs 0.071, P = 0.49; and 0.085 vs 0.082, P = 0.90), and TLR9 (-1237T/C, 0.154 vs 0.148, P = 0.82) genes between controls and patients, respectively. There was no evidence that the variant TLR alleles were associated with disease phenotype. However, combination of the datasets of published studies with our dataset confirmed that the TLR4 polymorphism 299G (P = 0.0005; OR of 1.42 [95% CI 1.17-1.74]) and the TLR9 polymorphism -1237C (P = 0.0416; OR of 1.33 [95% CI 1.01-1.75]) are associated with CD. CONCLUSIONS There was no evidence that the above variants of the TLR2, TLR4 and TLR9 genes are major risk factors for CD or influence disease phenotype in our New Zealand case-control study. Nevertheless, the significance of the TLR4 299G and TLR9-1237C associations with CD worldwide was confirmed by a meta-analysis test using our datasets and datasets from previously published studies.
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Affiliation(s)
- Jiwon Hong
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Duan ZX, Zhu PF, Dong H, Gu W, Yang C, Liu Q, Wang ZG, Jiang JX. Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock 2007; 28:160-4. [PMID: 17529905 DOI: 10.1097/shk.0b013e31803df782] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Toll-like receptor 4 (TLR4) is the central signaling receptor for lipopolysaccharide (LPS) in mammals. This study was designed to investigate the functional significance of the G11367C polymorphism, which is a novel variant we identified in the 3' untranslated region of TLR4 gene in Chinese Han population. Three hundred seventy healthy volunteers were selected. The TLR4/11367 polymorphism was genotyped using single-tube bidirectional allele-specific amplification method. The TLR4 protein expression on peripheral leukocytes and plasma tumor necrosis factor alpha levels were determined by means of flow cytometry and enzyme-linked immunosorbent assay. The post-transcriptional effect of the 11367 polymorphism was evaluated by means of reporter gene assay and real-time quantitative polymerase chain reaction. The G11367C polymorphism is a common allele in Chinese Han population, with minor allele frequency of 14.7%. In response to ex vivo LPS stimulation, the TLR4 expression on the surface of peripheral leukocytes and the plasma tumor necrosis factor alpha levels were significantly lower in carriers of 11367C variant allele than in carriers of 11367G allele. This association was allele dose dependent. We also found that the activity and the mRNA expression of luciferase was significantly smaller in human embryonic kidney 293 cells transfected with construct containing 11367C allele than in those transfected with construct containing 11367G allele. Together, these results suggest that the TLR4/11367 polymorphism may be a functional single nucleotide polymorphism, which could attenuate the LPS-induced transmembrane signaling through the alteration of post-transcriptional regulation of 3' untranslated region and target gene expression.
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Affiliation(s)
- Zhao-xia Duan
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Daping, Chongqing 400-042, China
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Kang ES, Lee J. Genotypic analysis of Asp299Gly and Thr399Ile polymorphism of Toll-like receptor 4 in systemic autoimmune diseases of Korean population. Rheumatol Int 2007; 27:887-9. [PMID: 17235555 DOI: 10.1007/s00296-007-0311-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2006] [Accepted: 12/21/2006] [Indexed: 10/23/2022]
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Kato I, Canzian F, Plummer M, Franceschi S, van Doorn LJ, Vivas J, Lopez G, Lu Y, Gioia-Patricola L, Severson RK, Schwartz AG, Muñoz N. Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci 2007; 52:254-61. [PMID: 17171451 DOI: 10.1007/s10620-006-9303-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Accepted: 03/05/2006] [Indexed: 12/13/2022]
Abstract
As Helicobacter pylori (HP) is a Gram-negative bacterium, we investigated the associations between several functional polymorphisms in genes involved in lipopolysaccharide (LPS) signaling and the prevalence of various stages of gastric premalignant lesions in a Venezuelan population. The two NOD2 polymorphisms, del3020insC and Gly908Arg, were too infrequent to study their associations with gastric lesions. The risk of intestinal metaplasia (IM) was significantly increased among subjects with the CD14 T-260 allele compared to those without this allele. A similar, but nonsignificant increase in risk for dysplasia was observed among homozygotes of this allele. There was no association between TLR4 Asp299Gly polymorphism and any type of lesions, except for a slight nonsignificant increase in risk of IM associated with the AA genotype among subjects with a higher histological HP score. These results suggest that genetic polymorphisms in HP LPS signaling may be implicated in the development of intermediate stages of gastric premalignant lesions.
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Affiliation(s)
- Ikuko Kato
- Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, Michigan 48201, USA.
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Riis L, Vind I, Vermeire S, Wolters F, Katsanos K, Politi P, Freitas J, Mouzas IA, O'Morain C, Ruiz-Ochoa V, Odes S, Binder V, Munkholm P, Moum B, Stockbrügger R, Langholz E. The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel Dis 2007; 13:24-32. [PMID: 17206636 DOI: 10.1002/ibd.20047] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM The aetiology of inflammatory bowel disease (IBD) is unknown, but it has become evident that genetic factors are involved in disease susceptibility. Studies have suggested a north-south gradient in the incidence of IBD, raising the question whether this difference is caused by genetic heterogeneity. We aimed to investigate the prevalence of polymorphisms in CARD15 and TLR4 and occurrence of anti-Saccharomyces cerevisiae (ASCA) and antineutrophil cytoplasmic antibodies (pANCA) in a European population-based IBD cohort. METHODS Individuals from the incident cohort were genotyped for three mutations in CARD15 and the Asp299gly mutation in TLR4. Levels of ASCA and pANCA were assessed. Disease location and behaviour at time of diagnosis was obtained from patient files. RESULTS Overall CARD15 mutation rate was 23.9% for CD and 9.6% for UC patients (P < 0.001). Mutations were less present in the Scandinavian countries (12.1%) versus the rest of Europe (32.8%) (P < 0.001). Overall population attributable risk was 11.2%. TLR4 mutation rate was 7.6% in CD, 6.7% in UC patients and 12.3% in healthy controls (HC), highest among South European CD patients and HC. ASCA was seen in 28.5% of CD patients with no north-south difference, and was associated with complicated disease. pANCA was most common in North European UC patients and not associated with disease phenotype. CONCLUSION The prevalence of mutations in CARD15 varied across Europe, and was not correlated to the incidence of CD. There was no association between mutations in TLR4 and IBD. The prevalence of ASCA was relatively low; however related to severe CD.
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Affiliation(s)
- Lene Riis
- Department of Medical Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark.
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Yoon HJ, Choi JY, Kim CO, Park YS, Kim MS, Kim YK, Shin SY, Kim JM, Song YG. Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia. J Korean Med Sci 2006; 21:979-982. [PMID: 17179672 PMCID: PMC2721950 DOI: 10.3346/jkms.2006.21.6.979] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2006] [Accepted: 03/30/2006] [Indexed: 01/15/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern-recognition receptors that are important in innate immune responses to bacterial infection. The purpose of this study is to describe the prevalence of TLRs genetic variations in the bacteremic patients in Korea. A total of 154 patients with bacteremia and 179 healthy volunteers were included. The Asp299Gly and Thr399Ile allele of the TLR4 gene and Arg753Gln and Arg677Trp allele of the TLR2 gene were tested by PCR-RFLP. The DNA sequences were determined to confirm the PCR-RFLP results. Contrary to the expectation, no genetic polymorphisms were detected in both groups of this study, suggesting that it is very rare in Korean.
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Affiliation(s)
- Hee Jung Yoon
- Department of Internal Medicine, Eulji University, College of Medicine, Daejeon, Korea
| | - Jun Yong Choi
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Chang Oh Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Seon Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Myoung Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young Keun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - So Youn Shin
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - June Myung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young Goo Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- AIDS Research Institute, Yonsei University College of Medicine, Seoul, Korea
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Shiraki R, Inoue N, Kobayashi S, Ejiri J, Otsui K, Honjo T, Takahashi M, Hirata KI, Yokoyama M, Kawashima S. Toll-like receptor 4 expressions on peripheral blood monocytes were enhanced in coronary artery disease even in patients with low C-reactive protein. Life Sci 2006; 80:59-66. [PMID: 17045300 DOI: 10.1016/j.lfs.2006.08.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2006] [Revised: 07/28/2006] [Accepted: 08/17/2006] [Indexed: 11/25/2022]
Abstract
Toll-like receptors (TLRs) play important roles in the pathogenesis of atherosclerosis. On the other hand, serum high sensitivity C-reactive protein (hsCRP) is known as an independent coronary risk factor, but cardiovascular events do occur even in low hsCRP levels. We investigated whether the TLR4 expression levels on human peripheral blood monocytes were associated with serum hsCRP levels or the occurrence of coronary artery diseases (CAD). One hundred CAD patients and 100 non-CAD subjects were enrolled. There were 72 non-CAD subjects and 53 CAD patients with low serum hsCRP levels. Among the low-hsCRP subjects, the TLR4 expression levels were higher in CAD patients than in non-CAD subjects (P < 0.05, after being adjusted for other risk factors). Moreover, TLR4 expression levels in stable angina pectoris (SAP) patients were elevated compared with those in non-CAD subjects (P < 0.05), and those in acute coronary syndrome patients were higher than SAP patients even in low-hsCRP subjects (P < 0.01). In conclusion, the TLR4 expression levels on peripheral blood monocytes in CAD patients were higher than those in non-CAD subjects and correlated with disease activity, even in low-hsCRP subjects. The combined measurement of serum hsCRP and the TLR4 expression on peripheral blood monocytes, especially among low-hsCRP subjects, may become a new coronary risk marker.
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Affiliation(s)
- Rio Shiraki
- Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
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Jilling T, Simon D, Lu J, Meng FJ, Li D, Schy R, Thomson RB, Soliman A, Arditi M, Caplan MS. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2006; 177:3273-82. [PMID: 16920968 PMCID: PMC2697969 DOI: 10.4049/jimmunol.177.5.3273] [Citation(s) in RCA: 326] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Bacteria are thought to contribute to the pathogenesis of necrotizing enterocolitis (NEC), but it is unknown whether their interaction with the epithelium can participate in the initiation of mucosal injury or they can act only following translocation across a damaged intestinal barrier. Our aims were to determine whether bacteria and intestinal epithelial TLR4 play roles in a well-established neonatal rat model and a novel neonatal murine model of NEC. Neonatal rats, C57BL/6J, C3HeB/FeJ (TLR4 wild type), and C3H/HeJ (TLR4 mutant) mice were delivered by Cesarean section and were subjected to formula feeding and cold asphyxia stress or were delivered naturally and were mother-fed. NEC incidence was evaluated by histological scoring, and gene expression was quantified using quantitative real-time PCR from cDNA generated from intestinal total RNA or from RNA obtained by laser capture microdissection. Spontaneous feeding catheter colonization or supplementation of cultured bacterial isolates to formula increased the incidence of experimental NEC. During the first 72 h of life, i.e., the time frame of NEC development in this model, intestinal TLR4 mRNA gradually decreases in mother-fed but increases in formula feeding and cold asphyxia stress, correlating with induced inducible NO synthase. TLR4, inducible NO synthase, and inflammatory cytokine induction occurred in the intestinal epithelium but not in the submucosa. NEC incidence was diminished in C3H/HeJ mice, compared with C3HeB/FeJ mice. In summary, bacteria and TLR4 play significant roles in experimental NEC, likely via an interaction of intraluminal bacteria and aberrantly overexpressed TLR4 in enterocytes.
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Affiliation(s)
- Tamas Jilling
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Dyan Simon
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614
| | - Jing Lu
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Fan Jing Meng
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Dan Li
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Robert Schy
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Richard B. Thomson
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
| | - Antoine Soliman
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Moshe Arditi
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Michael S. Caplan
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60614
- Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201
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Werners AH, Bull S, Vendrig JC, Smyth T, Bosch RR, Fink-Gremmels J, Bryant CE. Genotyping of Toll-like receptor 4, myeloid differentiation factor 2 and CD-14 in the horse: An investigation into the influence of genetic polymorphisms on the LPS induced TNF-α response in equine whole blood. Vet Immunol Immunopathol 2006; 111:165-73. [PMID: 16476493 DOI: 10.1016/j.vetimm.2005.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2005] [Revised: 11/29/2005] [Accepted: 12/22/2005] [Indexed: 10/25/2022]
Abstract
The inter- and intra-species differences in the response to lipopolysaccharides (LPS) are well recognised in mammalian species. It has been hypothesized that these differences can be attributed to genetic polymorphisms in the components involved in LPS signal transduction. These components include the cluster of differentiation factor 14 (CD-14), a membrane bound protein on the surface of mononuclear cells that recognises LPS and a receptor complex consisting of Toll-like receptor-4 (TLR-4) and myeloid differentiation factor-2 (MD-2). Sequencing of these three proteins in humans and mice revealed that all three are susceptible to polymorphic alterations, influencing the response to LPS. Previous experiments in the horse showed large inter-individual variations in the response to LPS. With the aim to assess this inter-individual variation, we performed a whole blood assay in 10 healthy horses as a functional assay to study the responsiveness to LPS. In 3 out of the 10 horses, LPS-induced TNF-alpha production was significantly lower compared to the overall mean. Subsequently the entire cDNA sequence encoding for the TLR-4, MD-2 and CD-14 protein was documented for each horse. Although mutations were observed in the sequence of TLR-4, these could not be related to an altered response to LPS in the concentration used in this study, as determined in the whole blood assay. Despite the various mutations found in the TLR-4 receptor protein, no alterations could be found in either the MD-2 or CD-14 gene, which are obviously more conserved structures.
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Affiliation(s)
- A H Werners
- Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 16, 3584 CM, Utrecht, The Netherlands.
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Lakatos PL, Fischer S, Claes K, Kovacs A, Molnar T, Altorjay I, Demeter P, Tulassay Z, Palatka K, Papp M, Rutgeerts P, Szalay F, Papp J, Vermeire S, Lakatos L. DLG5 R30Q is not associated with IBD in Hungarian IBD patients but predicts clinical response to steroids in Crohn's disease. Inflamm Bowel Dis 2006; 12:362-368. [PMID: 16670524 DOI: 10.1097/01.mib.0000217336.38312.09] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Recent data suggest that haplotypic variants of the DLG5 gene on 10q23 are associated with susceptibility to inflammatory bowel disease (IBD) in Germany. In view of the geographical differences in frequency of genetic markers and the absence of data in Central European patients, our aim was to determine the DLG5 R30Q variant in Hungarian IBD patients. MATERIALS AND METHODS We investigated 773 unrelated IBD patients (age 38.1 +/- 10.3 years; duration, 8.8 +/- 7.5 years; Crohn's disease [CD]: 639; male/female, 309/330; duration, 8.4 +/- 7.1 years; ulcerative colitis [UC]: 134; male/female, 63/71; duration, 10.6 +/- 8.9 years) and 150 healthy subjects. DLG5 R30Q and TLR4 D299G variants were tested by polymerase chain reaction/restriction fragment length polymorphism. DNA was screened for NOD2/CARD15 mutations by denaturing high-performance liquid chromatography. Detailed clinical phenotype was determined by reviewing the medical charts. RESULTS The frequency of the R30Q variant allele was not significantly different in IBD (22.0%), CD (20.8%), and UC (27.6%) patients compared with healthy control subjects (28.0%). In CD, the 113A variant allele was associated with steroid resistance (16.3% vs noncarriers, 7.6%; odds ratio [OR], 2.4; 95% CI 1.3-4.5; P = 0.013). In a logistic regression model carriage of DLG5 R30Q, perianal involvement and frequent relapses were independently associated with steroid resistance. No phenotype-genotype associations were found in UC patients, although a trend toward more extensive disease was observed in carriers of the variant allele (OR = 2.1; 95% CI 0.95-4.4; P = 0.07). CONCLUSIONS The present data strongly contrast previous data from Germany. DLG5 113A is not associated with disease susceptibility, but there was a tendency for this allele to confer resistance to steroids. Further studies are required to evaluate the significance of DLG5 in other populations from geographically diverse regions.
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Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12:1829-1841. [PMID: 16609988 PMCID: PMC4087507 DOI: 10.3748/wjg.v12.i12.1829] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 10/20/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is only partially understood. Various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors (e.g. NOD2/CARD15, SLC22A46A5 and DLG5). The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083 Budapest, Hungary.
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Hua KL, Xia B, Li C, Guo QS. No association between Toll-like receptor-4 gene polymorphism and Helicobacter pylori infection in chronic gastritis. Shijie Huaren Xiaohua Zazhi 2006; 14:718-721. [DOI: 10.11569/wcjd.v14.i7.718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIMS: To study the distribution of Toll-like receptor-4 (TLR4) gene Asp299Gly poly-morp-hism and to define association between TLR4 genotype and Helicobacter Pylori asso-ciated chronic gastritis in Han Chinese of Hubei province.
METHODS: One hundred and fifteen patients with chronic superficial gastritis and 264 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for TLR4 gene Asp299Gly polymorphism. Meanwhile, H. pylori infection was also detected in all the individuals.
RESULTS: The rate of H. pylori infection was 89.6% in patients with chronic superficial gast-ritis, and 61.7% in the healthy controls, and there was significant difference between them (P < 0.000 1, OR = 5.319, 95%CI: 2.784-10.162). All the individuals had the same TLR4 Asp-299Gly genotypes (AA). The distributions of the genotypes and allele frequencies of TLR4 Asp299Gly were not significantly diffe-rent between gastritis patients and healthy controls.
CONCLUSION: There is no marked correlation between TLR4 Asp299Gly polymorphism and H. pylori associated chronic gastritis in Han Chinese of Hubei province.
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Guo Q, Zhu J, Xia B. Polymorphism of CD14 gene but not the mutation of TLR4 gene is associated with colorectal cancer in Chinese patients. J Gastroenterol Hepatol 2006; 21:92-7. [PMID: 16706818 DOI: 10.1111/j.1440-1746.2005.04156.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Toll-like receptor 4 and CD14 are components of the lipopolysaccharide receptor complex. Our study aimed to investigate an association between TLR4 Asp299Gly and CD14-260 polymorphisms in Chinese patients with colorectal cancer. METHOD By a method of polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP), we genotyped TLR4 Asp299Gly and CD14-260 polymorphisms in 110 unrelated patients with colorectal cancer and 160 healthy controls from the Chinese Han population. RESULTS We found significant differences in CD14 genotypes between healthy controls and patients with colorectal cancer. The frequency of the C/C genotype in healthy controls (15.6%) was significantly lower than in the group of colorectal cancer patients (32%). The frequency of the C/T genotype in healthy controls (48.1%) was significantly higher than that in the group of colorectal cancer patients (31%). No TLR4 Asp299Gly mutation was detected in any patients or healthy controls in the Chinese Han population. CONCLUSIONS These findings indicated that the polymorphism of CD14 but not TLR4 Asp299Gly mutation was associated with Chinese patients with colorectal cancer, and the CD14 gene may contribute to the predisposition to colorectal cancer. Screening for the CD14 C-260T genotype is likely to be a useful tool for risk assessment or prognostication for colorectal cancer in the Chinese Han population.
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Affiliation(s)
- Qiusha Guo
- Department of Internal Medicine, Research Center of Digestive Diseases, Wuhan University Zhongnan Hospital, Wuhan, China
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Guo QS, Xia B, Jiang Y, Morré SA, Cheng L, Li J, Crusius JBA, Peña AS. Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad Med J 2005; 81:526-9. [PMID: 16085746 PMCID: PMC1743318 DOI: 10.1136/pgmj.2004.030825] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Toll-like receptor 4 and CD14 are the components of the lipopolysaccharide receptor complex. The aim of this study was to investigate the associations between polymorphisms TLR4 Asp299Gly and CD14 C-260T and Chinese patients with ulcerative colitis (UC). METHODS Using a polymerase chain reaction based restriction fragment length polymorphism, the study genotyped polymorphisms TLR4 Asp299Gly and CD14 C-260T in 114 patients with UC and 160 healthy controls in the Chinese Han population. Moreover a comparison was made with 170 healthy Dutch white subjects. RESULTS No TLR4 Asp299Gly mutation was detected in any patients or healthy controls in the Chinese Han population, which was similar to Japanese subjects, but the mutation occurred in 10% of the Dutch white subjects. There were no significant differences of CD14 genotypes between healthy controls and the patients with UC.
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Affiliation(s)
- Q S Guo
- Department of Internal Medicine and Geriatrics, Research Centre of Digestive Diseases, Zhongnan Hospital, Wuhan University Medical School, Wuhan, PR of China
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Fries W, Renda MC, Lo Presti MA, Raso A, Orlando A, Oliva L, Giofré MR, Maggio A, Mattaliano A, Macaluso A, Cottone M. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. Am J Gastroenterol 2005; 100:2730-2736. [PMID: 16393227 DOI: 10.1111/j.1572-0241.2005.00325.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE A defect of gastrointestinal barrier function is considered to represent an important step in the pathogenesis of Crohn's disease (CD) but the mechanisms leading to an increased intestinal permeability (IP) are poorly understood. Since IP is influenced by pro-inflammatory mediators, it seems likely that a genetically determined abnormal immune response may lead to a loss of barrier function. METHODS In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives). RESULTS Forty-eight percent of CD patients and 40% of their healthy relatives were found to have an abnormal IP compared to 5% of an appropriate control population (p < 0.0001). IP, however, was not associated with the L1007finsC mutation of the NOD2/CARD15 or the D299G variant of the TLR-4 gene. Allele frequency of the only L1007finsC mutation of CARD15 was significantly increased in patients (8.7%, p < 0.003) and in relatives (8.3%, p < 0.024) compared with controls (2.4%), whereas the D299G variant of the TLR-4 gene was found to be increased only in relatives (8.3%, p < 0.022), but not in patients (4.3%) compared with the control population (1.7%). CONCLUSIONS There was no association between IP and genetic markers. Our findings showed a very high proportion of healthy first-degree relatives to bare alterations suggested to constitute determinants of CD. Mutations of NOD2/CARD15 or TLR-4, however, do not lead to permeability defects emphasizing the importance of additional environmental and/or genetic factors for pathogenesis.
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Affiliation(s)
- Walter Fries
- Dipartimento di Medicina Interna e Terapia Medica, Università di Messina, Messina, Italy
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Saçkesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E, Soyer OU, Adalioglu G, Tuncer A, Birben E, Oner C, Kalayci O. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy 2005; 60:1485-92. [PMID: 16266379 DOI: 10.1111/j.1398-9995.2005.00874.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Endotoxin, with its potential to enhance type 1 immunity, is a significant player in the hygiene hypothesis. The combined effects of the genetic variants of various molecules in the endotoxin response pathway on asthma related phenotypes are largely unknown. OBJECTIVE To investigate the effects of the genetic variants of CD14 and TLR4 genes on asthma phenotypes in a large number of asthmatic children. METHODS 613 asthmatic children were genotyped at the CD14-C159T, TLR4-A896G and TLR4-C1196T loci. IgE, eosinophil numbers and FEV1 were compared in 327 children who were not on any controller medications and were symptom free. Multivariate logistic regression was used to determine the factors associated with total IgE. RESULTS Among children with atopic asthma, total IgE levels were significantly different among the three genotypes in the co-dominant model [CC: 435 kU/l (interquartile range: 146-820); CT: 361 (140-710); TT 204 (98-435), P = 0.035]. TT genotype was significantly and independently associated with lower IgE levels (OR: 0.5 95%; CI = 0.28-0.90, P = 0.021). Both TLR4-A896G and TLR4-C1196T polymorphisms were more frequent in the mild asthma group with atopy (P = 0.032, 0.018, respectively). The combined effects of the genetic variants in CD14 and TLR4 genes did not improve the observed associations. CONCLUSION Our study demonstrates that the CD14-C159T promoter variant influences total IgE levels and also indicates that the T allele has a more profound effect on total IgE in children with atopic asthma. Polymorphisms in the TLR4 gene may be associated with milder forms of disease in atopic asthmatics in the population studied.
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Affiliation(s)
- C Saçkesen
- School of Medicine, Pediatric Allergy and Asthma Unit, Hacettepe University, Hacettepe, Ankara, Turkey
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Nakada TA, Hirasawa H, Oda S, Shiga H, Matsuda KI, Nakamura M, Watanabe E, Abe R, Hatano M, Tokuhisa T. Influence of Toll-Like Receptor 4, CD14, Tumor Necrosis Factor, and Interleukine-10 Gene Polymorphisms on Clinical Outcome in Japanese Critically Ill Patients. J Surg Res 2005; 129:322-8. [PMID: 16051275 DOI: 10.1016/j.jss.2005.05.020] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2005] [Revised: 04/01/2005] [Accepted: 05/23/2005] [Indexed: 01/31/2023]
Abstract
The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.
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Affiliation(s)
- Taka-Aki Nakada
- Department of Emergency and Critical Care Medicine, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan.
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