Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 28-28 ◽  
Author(s):  
Lori A Kelly ◽  
Ali H Zaidi ◽  
Mark Barlek ◽  
Rachael Kreft ◽  
Ashten Omstead ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Direct Proof ◽  
Acid Reflux ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Molecular Sequence ◽  
E Coli ◽  
Post Surgery ◽  
Tlr Signaling Pathway

28 Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.

Toll-Like Receptor Signaling Pathway In Chronic Lymphocytic Leukemia: Distinct Gene Expression Profiles of Potential Pathogenetic Significance In Specific Subsets of Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 44-44
Author(s):  
Eleni Arvaniti ◽  
Stavroula Ntoufa ◽  
Nikos Papakonstantinou ◽  
Tasoula Touloumenidou ◽  
Nikolaos Laoutaris ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Signaling Pathway ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Molecular Features ◽  
Specific Stimulation ◽  
Tlr Signaling Pathway

Abstract Abstract 44 The role of antigen in the development of CLL is underscored by the biased immunoglobulin (IG) gene repertoire expressed by the malignant clones, the prognostic implications of B-cell receptor (BcR) structure and the identification of subsets of patients with quasi-identical, stereotyped BcRs. The structural homology of BcRs implies a role for a limited set of antigens or structurally related epitopes in leukemogenesis. Antigen recognition and host defense rely on multiple mechanisms acting synergistically in order to mount an effective immune response. These include specific stimulation through the BcR and non-specific stimulation through innate immune receptors, of which the major class is the Toll-like receptor (TLR) family. The available data on TLR expression in CLL are limited and derive from small series of patients. In the present study we performed a systematic gene expression profiling of the TLR signaling pathway in a large series of 191 patients with CLL. The analysis extended from all TLRs known to be functional in normal B cells to adaptors, effectors, inhibitors and members of the NFKB, JNK/p38, NF/IL6, and IRF signaling pathways downstream of TLR signaling. In addition, differences in gene expression profiles were sought for among subgroups of cases defined by BcR molecular features, such as the repertoire and mutational status of the IG heavy variable (IGHV) genes or the expression of stereotyped BcRs. CD19+ B lymphocytes were negatively selected from peripheral blood samples. The gene expression profile of the TLR signalling pathway was determined by the RT2Profiler™ PCR Array kit (PAHS-018A array, SABiosciences). At cohort level, among the receptors, high expression was recorded for TLR7 and CD180, intermediate for TLR1, TLR6 and TLR10 and low expression for TLR2 and TLR9. TLR4 and TLR8 were characterized by low to undetectable expression, with significant variations between patients, while TLR3 and TLR5 were not expressed in any case. The vast majority of the adaptors (e.g. MyD88, TICAM1, TRAF6), the effectors (UBE2N) and the members of the NFKB, JNK/p38, NF/IL6, and IRF signaling pathways downstream of TLR signaling were intermediately to highly expressed, while the inhibitors of TLR activity (TOLLIP, SIGIRR/TIR8) were generally low to undetectable, suggesting that the TLRs signalling pathway is active in CLL. Further comparison in subgroups of cases carrying mutated vs. unmutated IGHV sequences (124 and 67 cases, respectively) revealed upregulation of CD80, CD86, IL6, IFNG and TLR4 and downregulation of TLR8 and NFKBIL1 in the mutated subgroup. Significant differences in gene expression profiles were also found in subgroups of cases with stereotyped receptors. Comparison of subset #4 (mutated IGHV4-34/1GKV2-30 BcR, 10 cases) vs. subset #1 (unmutated IGHV1/5/7-IGKV1(D)-39 BcR, 10 cases) vs. subset #8 (unmutated IGHV4-39/IGKV1(D)-39 BcR, 4 cases) revealed: (i) upregulation of TLR7 and NFKB1A and downregulation of CD86 and TLR4 in #1 vs #4 cases; (ii) upregulation of MAP4K4 and TLR4 and downregulation of NFKB1A and CD180 in #8 vs #1 cases; and, (iii) upregulation of LY96 and downregulation of RIPK2 and CD86 in #8 vs #4 cases. In conclusion, the TLR gene expression profile of CLL is consistent with derivation from antigen-experienced B cells. Significant variations were identified in different subgroups of cases defined by BcR molecular features, indicating distinctive activation patterns of the TLR signaling pathway, especially among cases assigned to subsets with stereotyped BcRs, with potential implications about the nature of the antigenic stimulation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hepatitis C Virus Nonstructural Protein 5A Modulates the Toll-Like Receptor-MyD88-Dependent Signaling Pathway in Macrophage Cell Lines

2007 ◽  
Vol 81 (17) ◽  
pp. 8953-8966 ◽  
Author(s):  
Takayuki Abe ◽  
Yuuki Kaname ◽  
Itsuki Hamamoto ◽  
Yoshimi Tsuda ◽  
Xiaoyu Wen ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Immune Cells ◽  
Cytokine Production ◽  
Toll Like Receptor ◽  
Macrophage Cell ◽  
Tlr Signaling ◽  
Tlr Signaling Pathway

ABSTRACT Hepatitis C virus (HCV) infection induces a wide range of chronic liver injuries; however, the mechanism through which HCV evades the immune surveillance system remains obscure. Blood dendritic cells (DCs) play a pivotal role in the recognition of viral infection and the induction of innate and adaptive immune responses. Several reports suggest that HCV infection induces the dysfunction of DCs in patients with chronic hepatitis C. Toll-like receptor (TLR) has been shown to play various roles in many viral infections; however, the involvement of HCV proteins in the TLR signaling pathway has not yet been precisely elucidated. In this study, we established mouse macrophage cell lines stably expressing HCV proteins and determined the effect of HCV proteins on the TLR signaling pathways. Immune cells expressing NS3, NS3/4A, NS4B, or NS5A were found to inhibit the activation of the TLR2, TLR4, TLR7, and TLR9 signaling pathways. Various genotypes of NS5A bound to MyD88, a major adaptor molecule in TLR, inhibited the recruitment of interleukin-1 receptor-associated kinase 1 to MyD88, and impaired cytokine production in response to TLR ligands. Amino acid residues 240 to 280, previously identified as the interferon sensitivity-determining region (ISDR) in NS5A, interacted with the death domain of MyD88, and the expression of a mutant NS5A lacking the ISDR partially restored cytokine production. These results suggest that the expression of HCV proteins modulates the TLR signaling pathway in immune cells.

scholarly journals Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1415 ◽  
Author(s):  
Eun-Young Kwon ◽  
Myung-Sook Choi
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Low Grade ◽  
Toll Like Receptor ◽  
High Fat ◽  
Gene Expressions ◽  
Tlr Signaling ◽  
Low Grade Inflammation ◽  
Tlr Signaling Pathway

This study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on the role of luteolin in the modulation of the Toll-like receptor (TLR) signaling pathway. C57BL/6J mice were fed a normal, high-fat, or high-fat + 0.005% (w/w) luteolin diet for 16 weeks. Luteolin improved chronic low-grade inflammation by modulating the TLR signaling pathway, resulting in reduced pro-inflammatory cytokines and macrophage accumulation. A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of luteolin-treated mice, which was linked to attenuation of hepatic lipotoxicity by increasing free fatty acid (FFA) flux to the WAT. Luteolin prevented fibrosis by decreasing extracellular matrix accumulation and cathepsin gene expressions, while enhancing the hepatic antioxidant system. Emr1 and Ccl7, important markers inducing low-grade inflammation, were affected by advanced age and greater body weight, which were normalized by luteolin treatment. Luteolin improved insulin resistance by normalizing pancreatic islet dysfunction and differentially modulating the plasma glucagon-like peptide-1 and gastric inhibitory polypeptide levels. Our results suggest that luteolin ameliorates diet-induced obesity and its comorbidities. Overall, this study provides novel insights into the effect of luteolin on the links among adiposopathy, insulin resistance, hepatic steatosis, and fibrosis.

scholarly journals Evaluation of E. coli Nissle1917 derived metabolites in modulating key mediator genes of the TLR signaling pathway

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sheyda Damoogh ◽  
Mehrad Vosough ◽  
Shima Hadifar ◽  
Masoumeh Rasoli ◽  
Ali Gorjipour ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Signaling Pathway ◽  
Tlr Signaling ◽  
E Coli ◽  
Tnf Α ◽  
Different Types ◽  
Health And Illness ◽  
Inflammatory Bowel ◽  
Dose Dependent ◽  
Tlr Signaling Pathway

Abstract Objective Gut-microbiota plays key roles in many aspects like the health and illness of humans. It's well proved that modification of gut microbiota by probiotics is useful for improving inflammatory bowel disease (IBD) conditions. According to recent studies, different types of bacterial metabolites can affect immune cells and inflammation conditions. The present study aimed to evaluate the anti-inflammatory effects of metabolites of E. coli Nissle1917. Results The cell-free supernatant could modulate TNF-α production and affected many crucial mediators in the Toll-like receptor (TLR) signaling pathway. Also, supernatant showed significant dose-dependent properties in this regard. In this study, the TLR signaling pathway was found among probable mechanisms by which probiotics can affect inflammatory situations. These findings provide additional evidence on the use of probiotic metabolites for inhibiting and down-regulating numerous key mediator factors in the TLR signaling pathway. Aberrant or dysfunctional TLR signaling contributes to the development of acute and chronic intestinal inflammatory pathways in IBD. Therefore, finding a component that can affect this process might be considered for therapeutic targets in IBD patients.

The various components implied the diversified Toll-like receptor (TLR) signaling pathway in mollusk Chlamys farreri

2018 ◽  
Vol 74 ◽  
pp. 205-212 ◽  
Author(s):  
Mengqiang Wang ◽  
Lingling Wang ◽  
Zhihao Jia ◽  
Qilin Yi ◽  
Linsheng Song
Keyword(s):  
Signaling Pathway ◽  
Chlamys Farreri ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Tlr Signaling Pathway

scholarly journals Upregulated genes in toll-like receptor (TLR) signaling pathway in periodontitis-affected gingival tissues

2014 ◽  
Vol 04 (01) ◽  
pp. 22-28 ◽  
Author(s):  
Daisuke Abe ◽  
Takehiko Kubota ◽  
Toshiya Morozumi ◽  
Hiromasa Yoshie
Keyword(s):  
Signaling Pathway ◽  
Toll Like Receptor ◽  
Tlr Signaling ◽  
Upregulated Genes ◽  
Tlr Signaling Pathway
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