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Background: Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progressi...
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Background: Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progression and its accompanying inflammatory response. We determined the association of atherosclerotic lesions and TLR mRNA expression in different aortic sites. We also assessed the effects of fluvastatin (Flu) treatment on TLR expression and plaque characteristics. Methods: Male rabbits, fed with an atherogenic diet for a duration of 3 months, were screened for advanced atherosclerotic lesions in the aorta. Additional animals received normal diet or normal diet plus Flu for 1 additional month. TLR mRNA expression in various thoracic and abdominal aortic segments was assessed, together with atherosclerotic changes. Results: After high lipid diet, the atherosclerotic burden increased more in the abdominal than in the thoracic aorta; TLR2, 3, 4, and 8 also increased significantly. Flu decreased atherosclerotic plaque, calcium deposition, lipid cores, intraplaque hemorrhage, erythrocyte membranes, endothelial cells, and macrophage infiltration, while increasing smooth muscle cells in plaques of both aortic segments; it also lowered TLR2, 3, 4, and 8 expression in all aortic segments to a stronger degree than resumption of normal diet. There was a strong association between blood and tissue parameters during experimental period and finally a strong correlation found between these parameters with mRNA of TLR2, 3, 4, and 8 in various stages. Conclusion: For the first time TLR2, 3, 4, and 8 mRNA expression is prospectively explored after hypercholesterolemic diet in the rabbit model. TLR2, 3, 4, and 8 mRNA expression is strongly upregulated and correlates with the progression of atherosclerosis in the aorta. Flu significantly inhibited this progress and reduced inflammation via TLR downregulation which was strongly associated with regression of plaque morphology and atherosclerosis promoting factors. (C) 2017 S. Karger AG, Basel
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Aim Expression of toll-like receptor (TLR) 2 subfamily genes, including genes encoding TLR1, TLR2, TLR6 and TLR10, have been connected to allergy and asthma. This controlled study investigated the association of TLR1, TLR2 and TLR...
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Aim Expression of toll-like receptor (TLR) 2 subfamily genes, including genes encoding TLR1, TLR2, TLR6 and TLR10, have been connected to allergy and asthma. This controlled study investigated the association of TLR1, TLR2 and TLR6 gene polymorphisms with clinical characteristics and subsequent wheezing in young infants with bronchiolitis. Methods In all, 129 full-term infants hospitalised for bronchiolitis at the age of <6 months were clinically followed up until a mean age of 18 months. Genotyping of the TLR1 T1805G, TLR2 G2258A and TLR6 C745T polymorphisms was carried out by pyrosequencing and in 318 healthy, Finnish controls. Results There were no significant associations between TLR1, TLR2 or TLR6 genotypes and severity of bronchiolitis or risk of postbronchiolitis wheezing. TLR6 polymorphism was associated with allergy in univariate analyses. Minor allele frequency (MAF) in the TLR1 gene (17%) in the hospitalised children was similar to our Finnish controls, but different to European controls from other studies. MAF in the TLR6 gene was 50% versus 41% in both the Finnish and European controls. MAF in the TLR2 gene was low (3%) in study subjects and in both controls. Conclusion TLR2 subfamily gene polymorphisms were not associated with severity of bronchiolitis or risk of postbronchiolitis wheezing.
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Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs)...
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Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established. Here we show that keratinocytes constitutively express TLR1, 2, 3, 4, 5, 6, 9, and 10 mRNA, but not TLR7 and 8. Stimulation of keratinocytes with TLR3, 4, 5, and 9 ligands resulted in differential immune-associated responses. Tumor necrosis factor-alpha, CXC chemokine ligand 8 (CXCL8), CCL2, and C chemokine ligand 20 (CCL20) release was enhanced in response to all PAMPs tested, in a time- and dose-dependent manner. Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs. CCL27 production was selectively induced by poly-I:C and flagellin, whereas CXCL9 and CXCL10 were exclusively induced by CpG-ODNs and/or poly-I:C. Upregulation of ICAM-1, HLA-DR, HLA-ABC, FasR, and CD40 was mainly observed in response to poly-I:C, flagellin, and lipopolysaccharide. Furthermore, PAMP triggering resulted in the phosphorylation of phosphorylated-IkappaB alpha and in the nucleus translocation of NF-kappaB p65. Altogether, these findings stress an unexpectedly multifaceted role of keratinocytes in innate immunity as evident by their differential, TLR-mediated responses to PAMPs associated with different classes of pathogens.
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AimToll-like receptor (TLR) 1, 2, 6 and 10, the TLR2 subfamily, are known to be associated with immunity against tuberculosis. We evaluated whether polymorphisms in genes encoding TLR1, TLR2 and TLR6 were associated with osteitis ...
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AimToll-like receptor (TLR) 1, 2, 6 and 10, the TLR2 subfamily, are known to be associated with immunity against tuberculosis. We evaluated whether polymorphisms in genes encoding TLR1, TLR2 and TLR6 were associated with osteitis in infants who received the Bacillus Calmette-Guerin (BCG) vaccination soon after birth.
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Coronavirus disease 2019 (COVID-19) spreads all around the world and leads to several new infection cases and mortality. A better understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis could...
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Coronavirus disease 2019 (COVID-19) spreads all around the world and leads to several new infection cases and mortality. A better understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis could lead to more efficient therapeutic approaches. : The current study aimed to investigate the Toll-like receptors expression profile in peripheral blood mononuclear cells in COVID-19 patients in Iran. Patients and Methods: In this cross-sectional study, we evaluated 32 COVID-19 patients. At the admission time based on the disease severity patients were divided into two groups of severe and mild COVID-19. A group of 16 normal people was evaluated as the healthy control. Blood samples were collected before any treatment from patients at the admission time. Peripheral blood mononuclear cell isolation preformed on blood samples. RNA is extracted from human peripheral blood mononuclear cells and use for the cDNA synthesis. The expression level of TLR-3, 4, and 7 were evaluated by using semi-quantitative real-time polymerase chain reaction (PCR). Results: The patient’s mean age was 57.12±3.08 years and 15 (47%) were male. The background disorders represent two patients in the severe group with respiratory disorders, four patients with cardiovascular disease, and seven patients with diabetes. The TLRs expression levels represent a higher expression of TLR-4 in COVID-19 in comparison with controls for TLR-4 (P=0.007), TLR-3 and 7 also represent up-regulation however there were no statistically significant differences in the relative fold changes (RFCs) between groups for all other evaluated TLRs (P>0.05). Conclusion: The study highlights the importance of the TLR-4 in COVID-19 patients in expression level. Further studies for a clear conclusion about TLRs expression levels are recommended.
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Type 2 diabetes (T2DM) is characterized by hyperglycemia, dyslipidemia, and increased inflammation. Previously, we showed that high glucose (HG) induces Toll-like receptor (TLR) expression, activity, and inflammation via NF-kB fol...
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Type 2 diabetes (T2DM) is characterized by hyperglycemia, dyslipidemia, and increased inflammation. Previously, we showed that high glucose (HG) induces Toll-like receptor (TLR) expression, activity, and inflammation via NF-kB followed by cytokine release in vitro and in vivo. Here, we determined how HG-induced inflammation is affected by free fatty acids (FFA) in human monocytes. THP-1 monocytic cells, CD14~+ human monocytes, and transiently transfected HEK293 cells were exposed to various FFA (0-500 |xM) and glucose (5-20 mM) for evaluation of TLR2, TLR4, NF-kB, IL-lbeta, monocyte chemoattractant protein-1 (MCP-1), and superoxide release. In THP-1 cells, palmitate increased cellular TLR2 and TLR4 expression, generated reactive oxygen species (ROS), and increased NF-kB activity, IL-1beta, and MCP-1 release in a dose- and time-dependent manner. Similar data were observed with stearate and FFA mixture but not with oleate. Conversely, NADPH oxidase inhibitor treatment repressed glucose-and palmitate-stimulated ROS generation and NF-kB activity and decreased IL-lbeta and MCP-1 expression. Silencing TLR2, TLR4, and p47phox with small inhibitory RNAs (siRNAs) significantly reduced superoxide release, NF-kB activity, IL-lbeta, and MCP-1 secretion in HG and palmitate-treated THP-1 cells. Moreover, data from transient transfection experiments suggest that TLR6 is required for TLR2 and MD2 for TLR4 to augment inflammation in FFA- and glucose-exposed cells. These findings were confirmed with human monocytes. We conclude that FFA exacerbates HG-induced TLR expression and activity in monocytic cells with excess superoxide release, enhanced NF-kB activity, and induced proinflammatory factor release.
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Toll-like receptors (TLRs) are essential mediators of both innate and adaptive immunity by recognizing and eliciting responses upon invasion of pathogens. The response of TLRs must be stringently regulated as exaggerated expressio...
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Toll-like receptors (TLRs) are essential mediators of both innate and adaptive immunity by recognizing and eliciting responses upon invasion of pathogens. The response of TLRs must be stringently regulated as exaggerated expression of signalling components as well as pro-inflammatory cytokines can have devastating effects on the host, resulting in chronic inflammatory diseases, autoimmune disorders and aid in the pathogenesis of TLR-associated human diseases. Therefore, it is essential that negative regulators act at multiple levels within TLR signalling cascades, as well as through eliciting negative-feedback mechanisms in order to synchronize the positive activation and negative regulation of signal transduction to avert potentially harmful immunological consequences. This review explores the various mechanisms employed by negative regulators to ensure the appropriate modulation of both immune and inflammatory responses.
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PURPOSE OF REVIEW: Allergic and certain other inflammatory diseases have become more common in industrialized countries over the past few decades. One potential explanation for such trends is that with a decreased incidence of mic...
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PURPOSE OF REVIEW: Allergic and certain other inflammatory diseases have become more common in industrialized countries over the past few decades. One potential explanation for such trends is that with a decreased incidence of microbial exposures, as a result of modern public health practices, an important source of immune stimulation has been lost, with a consequent increase in inflammatory responses and their associated diseases. This review will focus on our current understanding of how microbial exposures impact on host immunity and the pathogenesis of allergic diseases. RECENT FINDINGS: In the past decade, it has become clear that a number of molecular interactions between immunocytes and microbial compounds are mediated by Toll-like receptors on host cells. Moreover, recent investigations have suggested that ligands for different Toll-like receptors have the potential both to inhibit and promote the development of allergic hypersensitivities and diseases. SUMMARY: On the basis of studies discussed herein, we speculate that physiological exposures to Toll-like receptor ligands have important yet complex effects on immune homeostasis and host susceptibility towards atopic diseases. Moreover, we anticipate that a fuller understanding of how physiological Toll-like receptor ligand exposures impact on immune development will lead to novel therapeutic interventions for the prevention and treatment of atopic diseases.
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SUMMARY: PURPOSE OF REVIEW The discovery that mammalian Toll-like receptors recognize microbial products and initiate innate immune responses to them has spawned a new field of biology, namely the study of molecular interactions l...
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SUMMARY: PURPOSE OF REVIEW The discovery that mammalian Toll-like receptors recognize microbial products and initiate innate immune responses to them has spawned a new field of biology, namely the study of molecular interactions linking microbial recognition to innate and adaptive immune responses. This field has grown very rapidly in recent years, due largely to recent advances in genetic technology. This review summarizes recent work in which genetic approaches have been used to identify novel and important facets of Toll-like receptor function.RECENT FINDINGS Recent genetic studies have uncovered a wealth of information relating to ligand-receptor interactions, Toll-like receptor gene regulation, signal transduction, dendritic cell activation and allele-phenotype associations.SUMMARY Information emerging from genetic studies of Toll-like receptors has improved our understanding of innate and acquired immunity. This improved understanding promises to facilitate the future development of novel therapies for many different inflammatory diseases including asthma, sepsis and atherosclerosis.
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The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivaria...
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The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.
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