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The Heterogeneous Allelic Repertoire of Human Toll-Like Receptor (TLR) Genes
"... Toll-Like Receptors (TLR) are critical elements of the innate arm of the vertebrate immune system. They constitute a multigenic family of receptors which collectively bind a diverse array of – exogeneous as well as endogeneous – ligands. An exponential burst of knowledge has defined their biological ..."
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Toll-Like Receptors (TLR) are critical elements of the innate arm of the vertebrate immune system. They constitute a multigenic family of receptors which collectively bind a diverse array of – exogeneous as well as endogeneous – ligands. An exponential burst of knowledge has defined their biological role in fight against infections and generation/modulation of auto-immune disorders. Hence, they could at least be conceptually recognized – despite being structurally unrelated – as innate counterparts to Major Histocompatibility Complex (MHC) molecules – equally recognizing antigenic ligands (albeit structurally more homogeneous i.e., peptides), again derived from self and/or non-self sources – preeminent this time in adaptive immunity. Our great disparities in face of infections and/or susceptibility to auto-immune diseases have provoked an intense search for genetic explanations, in part satisfied by the extraordinary MHC allelic repertoire. An equally in-depth and systematic analysis of TLR diversity is lacking despite numerous independent reports of a growing number of SNPs within these loci. The work described here aims at providing a preliminary picture of the allelic repertoire – and not purely SNPs – of all 10 human TLR coding sequences (with exception of TLR3) within a single cohort of up to 100 individuals. It
1 Role of IL-17A in the development of colitis-associated cancer
"... ow nloaded from 2Abstract A close relationship between inflammation and colon cancer has been widely accepted, and Interleukin (IL)-17A plays an important role in controlling colonic inflammation. However, the role of IL-17A has not yet been validated in colitis-associated cancer (CAC). This study ..."
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ow nloaded from 2Abstract A close relationship between inflammation and colon cancer has been widely accepted, and Interleukin (IL)-17A plays an important role in controlling colonic inflammation. However, the role of IL-17A has not yet been validated in colitis-associated cancer (CAC). This study aims to identify the effects of IL-17A in tumorigenesis utilizing IL-17A deficient mice in an experimental CAC model. CAC was induced in both the IL-17A deficient and C57BL/6 (WT) mice by injection of 12.5 mg/kg azoxymethane followed by three rounds of 1.7 % dextran sodium sulfate exposure to elicit colitis. On day 63 after the start of the study, mice were sacrificed. Colonic inflammation, proliferation and tumorigenesis were evaluated. Tumor numbers per mouse (1.43 vs. 5.80; p=0.02) and mean tumor size (1.17 mm vs. 3.58 mm; p=0.01) were significantly decreased in IL-17A deficient mice compared to WT mice. Furthermore, the inflammation and the proliferation scores of IL-17A deficient mice were significantly lower than WT mice. In the analysis of inflammatory mediators, IL-6, IFN-γ, TNF-α, and IL-17A were markedly decreased in IL-17A deficient mice compared to WT mice. In the
Advance Access publication February 21, 2012 Role of IL-17A in the development of colitis-associated cancer
"... A close relationship between inflammation and colon cancer has been widely accepted, and interleukin (IL)-17A plays an important role in controlling colonic inflammation. However, the role of IL-17A has not yet been validated in colitis-associated cancer (CAC). This study aims to identify the effect ..."
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A close relationship between inflammation and colon cancer has been widely accepted, and interleukin (IL)-17A plays an important role in controlling colonic inflammation. However, the role of IL-17A has not yet been validated in colitis-associated cancer (CAC). This study aims to identify the effects of IL-17A in tumorigenesis utilizing IL-17A-deficient mice in an experimental CAC model. CAC was induced in both the IL-17A-deficient and the C57BL/6 (wild-type, WT) mice by injection of 12.5 mg/kg azoxymethane followed by three rounds of 1.7 % dextran sodium sulfate exposure to elicit colitis. On day 63 after the start of the study, mice were sacrificed. Colonic inflammation, proliferation and tumorigenesis were evaluated. Tumor numbers per mouse (1.43 versus 5.80; P 5 0.02) and mean tumor size (1.17 versus 3.58 mm; P 5 0.01) were significantly decreased in IL-17A-deficient mice compared with WT mice. Furthermore, the inflammation and the proliferation scores of IL-17A-deficient mice were significantly lower than WT mice. In the analysis of inflammatorymediators, IL-6, interferon-g, tumor necrosis factor-a and IL-17A were markedly decreased in IL-17A-deficient mice compared withWTmice. In the western blot analysis, p-STAT3, cyclin D1, cyclin-dependent kinase 2, cyclin E, Glycogen synthase kinase 3-b and p-Akt were downregulated in IL-17A-deficient mice. Immunohistochemical staining with p-STAT3, Ki-67 and b-catenin revealed lower number of stained cells in IL-17A-deficient mice compared with WT mice. IL-17A ablation significantly decreases CAC tumorigenesis and thus may play an important role associated with chronic colitis.
Running Title: Association of Inflammation Genes with Prostate Cancer
"... 2 Background: Chronic inflammation is an important mechanism for the development and progression of prostate cancer. To better understand the potential relationship between genes in the inflammation pathway and prostate cancer (PC) risk, we evaluated variants in 16 candidate genes. Methods: A total ..."
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2 Background: Chronic inflammation is an important mechanism for the development and progression of prostate cancer. To better understand the potential relationship between genes in the inflammation pathway and prostate cancer (PC) risk, we evaluated variants in 16 candidate genes. Methods: A total of 143 tagging and amino acid altering single nucleotide polymorphisms
Carcinogenesis vol.29 no.7 pp.1334–1342, 2008
, 2008
"... doi:10.1093/carcin/bgn149 ..."
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BMC Cancer BioMed Central
, 2008
"... Research article Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer ..."
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Research article Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer
Reactive Oxygen Species Enhance TLR10 Expression in the
, 2010
"... Abstract: We investigated TLR10 expression in human monocytes, THP-1 cells, cultured in hypoxia (3 % O2). Levels of both TLR10 mRNA and protein in THP-1 cells cultured in hypoxia were significantly higher than those cultured in normoxia (20 % O2). We examined intracellular reactive oxygen species (R ..."
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Abstract: We investigated TLR10 expression in human monocytes, THP-1 cells, cultured in hypoxia (3 % O2). Levels of both TLR10 mRNA and protein in THP-1 cells cultured in hypoxia were significantly higher than those cultured in normoxia (20 % O2). We examined intracellular reactive oxygen species (ROS) content in hypoxic cells, and TLR10 expression in cells treated with hydrogen peroxide (H2O2), to determine whether the increase in TLR10 expression observed with hypoxia was due to an increase in intracellular ROS levels. We found that the level of intracellular ROS in cells subject to hypoxia was significantly higher than in normoxia. Experiments with ROS synthesis inhibitors revealed that hypoxia induced ROS production is mainly due to NADPH oxidase activity. TLR10 mRNA expression was increased by treatment with H2O2 at concentrations ranging from 50 to 250 μM. We screened the TLR10 promoter and found putative binding sites for transcription factors (TFs), such as NF-κB, NF-AT and AP-1. Next, we examined TF activities using a luciferase reporter assay. Activities of NF-κB, NF-AT and AP-1 in the cells treated with H2O2 were significantly higher than in untreated cells. The experiment with TF inhibitors revealed that ROS-induced upregulation of TLR10 expression is mainly
Association of the Innate Immunity and Inflammation Pathway with Advanced Prostate Cancer Risk
, 2012
"... Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 sin ..."
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Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.
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"... rof epithelial integrity results in activation of resident inflammatory cells bymicrobial invaders or endogenous ligands.When coupled with a failure of normal control mechanisms that limit leukocyte activation, a cascade is established that induces chronic inflammation and its consequences. Here, we ..."
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rof epithelial integrity results in activation of resident inflammatory cells bymicrobial invaders or endogenous ligands.When coupled with a failure of normal control mechanisms that limit leukocyte activation, a cascade is established that induces chronic inflammation and its consequences. Here, we outline this mechanistic framework and briefly review how alteration of innate immune response genes in murine models can provide insights into the potential microbial origins of diverse conditions including Crohn’s disease, psoriasis, atherosclerosis, diabetes, and liver cancer.
