Association between TLR2/TLR4 gene polymorphisms and COPD phenotype in a Greek cohort

Apostolou, Athanasios; Kerenidi, Theodora; Michopoulos, Alexandros; Gourgoulianis, K.; Noutsias, Michel; Germenis, Anastasios E.; Speletas, Matthaios

doi:10.1007/s00059-016-4510-9

Cited by 12 publications

(6 citation statements)

References 41 publications

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“…TLR2 and TLR4 polymorphisms were associated with various conditions such as asthma [40], pulmonary tuberculosis [32,41], Helicobacter pylori infection [42], as well as alterations in levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides [36]. They were also associated with susceptibility to COPD [25], the level and decline of lung function, an increased number of inflammatory cells in induced sputum of COPD patients [24], and an increased risk of COPD in smokers [43] or an earlier stage of COPD [44]. However, the ethnic context of polymorphisms as well as sample size should be considered regarding the results of the genetic association studies.…”

Section: Discussionmentioning

confidence: 99%

Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population

et al. 2021

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Heat shock protein 70 (Hsp70) engages Toll-like receptors (TLR) 2 and 4 when found in the extracellular compartment and contributes to inflammation in chronic obstructive pulmonary disease (COPD). Since there is growing evidence for the genetic risk factors for COPD, the gene expression of HSP70, TLR2 and TLR4 was determined, as well as the association between HSP70, TLR2 and TLR4 single nucleotide polymorphisms, (SNPs) and COPD. The gene expression was assessed in peripheral blood cells of 137 COPD patients and 95 controls by a quantitative polymerase chain reaction (qPCR), while a total of nine SNPs were genotyped by TaqMan allelic discrimination real-time PCR. HSP70 and TLR2 gene expression was increased in COPD patients compared to the controls, regardless of the disease severity and smoking status of participants. The rs6457452 SNP of HSP70 was associated with COPD, indicating the protective role of the T allele (OR = 0.46, 95% CI = 0.24–0.89, p = 0.022). Furthermore, COPD C/T heterozygotes showed a decreased HSP70 mRNA level compared to COPD C/C homozygotes. In conclusion, HSP70 and TLR2 may have a role in the pathogenesis of COPD, and the HSP70 rs6457452 variant might influence the genetic susceptibility to COPD in the Croatian population.

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Section: Discussionmentioning

confidence: 99%

Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population

et al. 2021

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“…TLRs are present in dendritic cells, alveolar macrophages, neutrophils, and epithelial cells, and they have been correlated to lung inflammation caused by COPD [3]. Among them, the expression of TLR2, TLR4, and TLR9 is elevated in monocytes and TLRs are associated with number of sputum neutrophils, secretion of pro-inflammatory cytokines, and lung function impairment [25][26][27]. This is a reflex of the immune dysfunction observed in COPD [28,29].…”

Section: Introductionmentioning

confidence: 99%

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells

et al. 2020

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COPD is a prevalent lung disease with significant impacts on public health. Affected airways exhibit pulmonary neutrophilia and consequent secretion of pro-inflammatory cytokines and proteases, which result in lung emphysema. Probiotics act as nonspecific modulators of the innate immune system that improve several inflammatory responses. To investigate the effect of Lactobacillus rhamnosus (Lr) on cigarette smoke (CS)-induced COPD C57Bl/6 mice were treated with Lr during the week before COPD induction and three times/week until euthanasia. For in vitro assays, murine bronchial epithelial cells as well as human bronchial epithelial cells exposed to cigarette smoke extract during 24 hours were treated with Lr 1 hour before CSE addition. Lr treatment attenuated the inflammatory response both in the airways and lung parenchyma, reducing inflammatory cells infiltration and the production of proinflammatory cytokines and chemokines. Also, Lr-treated mice presented with lower metalloproteases in lung tissue and lung remodeling. In parallel to the reduction in the expression of TLR2, TLR4, TLR9, STAT3, and NF-κB in lung tissue, Lr increased the levels of IL-10 as well as SOCS3 and TIMP1/2, indicating the induction of an anti-inflammatory environment. Similarly, murine bronchial epithelial cells as well as human bronchial epithelial cells (BEAS) exposed to CSE produced pro-inflammatory cytokines and chemokines, which were inhibited by Lr treatment in association with the production of anti-inflammatory molecules. Moreover, the presence of Lr also modulated the expression of COPD-associated transcription found into BALF of COPD mice group, i.e., Lr downregulated expression of NF-κB and STAT3, and inversely upregulated increased expression of SOCS3. Thus, our findings indicate that Lr modulates the balance between pro-and anti-inflammatory cytokines in human bronchial epithelial cells upon CS exposure and it can be a useful tool to improve the lung inflammatory response associated with COPD.

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“…However, the role of this system in COPD is not as clear. Aspects of the innate immune response are often demonstrably suppressed in COPD patients (Shaykhiev and Crystal, 2013), and TLR polymorphisms play a role in disease susceptibility and severity (Apostolou et al, 2016, Yu et al, 2016). Our work therefore also suggests a role for TLR pathways in the diagnosis, stratification, and treatment of COPD.…”

Section: Resultsmentioning

confidence: 99%

Pathway centrality in protein interaction networks identifies functional mediators of pulmonary disease

Park

Hescott

Slonim

2017

Preprint

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SummaryIdentification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We introduce the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. We find mediating pathways for three pulmonary diseases (asthma; bronchopulmonary dysplasia (BPD); and chronic obstructive pulmonary disease (COPD)) using pathway centrality. Mediating pathways shared by all three pulmonary disorders heavily favor inflammatory or immune responses and include specific pathways such as cytokine production, NF Kappa B, and JAK/STAT signaling. Disease-specific mediators, such as insulin signaling in BPD or homeostasis in COPD, are also highlighted. We support our findings, some of which suggest new treatment approaches, both with anecdotal evidence from the literature and via systematic evaluation using genetic interactions.peer-reviewed)

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Association between TLR2/TLR4 gene polymorphisms and COPD phenotype in a Greek cohort

Abstract: Our findings support the notion that the presence of innate immune SNPs, such as functional polymorphisms of TLRs along with MBL deficiency, might exert a protective effect on the COPD phenotype, similar with other immune-mediated disorders.

Cited by 12 publications

References 41 publications

Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population

Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population

Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: Relevance to inflammatory markers in human bronchial epithelial cells

Pathway centrality in protein interaction networks identifies functional mediators of pulmonary disease

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