Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria

Toll-like receptor (TLR) 4 is essential for the defense against infection with gram-negative pathogens, but reduced TLR4 expression has not been linked to altered disease susceptibility in humans. In mice, Tlr4 controls the mucosal response to Escherichia coli urinary tract infections. Inactivation of mouse Tlr4 causes an asymptomatic carrier state resembling asymptomatic bacteriuria (ABU). The present study compared neutrophil TLR4 expression levels between children with ABU (n=17) and age-matched control subjects (n=24), and significantly lower levels were detected in the patients with ABU. We also found elevated levels of the TLR4 adaptor protein TRIF and reduced levels of the TLR4-inhibitor SIGIRR in the patients with ABU, but MyD88 and TRAM levels were not significantly altered. Altered TLR4 and adaptor protein expression might impair TLR4 signaling and explain the weak mucosal response to urinary tract infection in patients who develop ABU rather than symptomatic disease.     

Functional polymorphisms of CD14 and toll-like receptor 4 in Taiwanese Chinese with Helicobacter pylori-related gastric malignancies

BACKGROUND/AIMS: Interindividual differences in degrees and extent of gastritis are responsible for the divergent outcomes after H. pylori infection. Cellular responses in gastric inflammation are mediated by lipopolysaccharide of H. pylori, which activate monocytes to express cytokine expression and growth factors via CD14 and toll-like receptor 4 (TLR4). Whether functional polymorphisms of TLR 4 and CD14 account for H. pylori-related gastric malignancies remains unknown. This study aimed to investigate the contribution of CD14 and TLR4 genotypes to the risk of H. pylori-related gastric malignancies in a Chinese population. METHODOLOGY: Genotyping for CD14 (-159C/T) and TLR4 (Asp 299Gly and Thr 399Ile) was performed in 70 patients with gastric mucosa-associated lymphoid tissue lymphoma (MALToma), 204 patients with non-cardia gastric adenocarcinoma (GAC), and 210 unrelated healthy controls. Distribution of genotype and allele frequencies among three groups was compared. RESULTS: The seropositive rate of H. pylori was significantly higher for non-cardia GAC (164/204, 80.4%) and MALToma (66/70, 94.3%) than controls (120/210, 57.5%, p<0.001). A complete absence of Gly or Ile variants was noted for all the studied subjects. The genotype frequencies of CD14 in controls were C/C, 25.7%, C/T, 48.6%, and T/T, 25.7%, and did not deviate from the Hardy-Weinberg equilibrium. The distribution of CD14 genotype did not differ significantly among GAC, MALToma patients, and controls. CONCLUSIONS: These data suggest no apparent association of CD14 polymorphisms with H. pylori-related gastric malignancy and provide evidence for race-specific distribution of TLR4 alleles in Chinese population.     

Reduced toll-like receptor 4 and substance P gene expression is associated with airway bacterial colonization in children

Neuro-immune interactions are increasingly relevant to human health and disease. The neuropeptide Substance P also has antibacterial activity and bears similarities to the innate immune antibacterial defensins. This suggests possible co-regulation of neuropeptide and innate immune mediators. In this study, non-bronchoscopic bronchoalveolar lavage (BAL) was performed on 69 children. BAL was examined for cellular profile, microbiology (bacteria, virus) and gene expression for TLRs 2, 3, 4; chemokine receptors (CCR3, CCR5, CXCR1); neurotrophins and neurokinin genes (TAC1, TAC3, CGRP, NGF). In children with bacterial colonization (n=10) there was an airway inflammatory response with increased BAL neutrophils, IL-8 protein, and CXCR1 expression. Substance P (TAC1) and TLR4 RNA expression were reduced in children with bacterial colonization. TLR3 mRNA was increased in 7.2% (n=5) children with rhinovirus, and there was a non-significant trend to increased TLR2. There is evidence for co-regulation of neurokinin (TAC1) and TLR4 gene expression in airway cells from children with airway bacterial colonization and their reduced expression may be associated with an impaired bacterial clearance.     

Candida-specific interferon-gamma deficiency and toll-like receptor polymorphisms in patients with chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) is a group of disorders, characterised by persistent mucocutaneous infections with Candida species. The underlying defect of CMC has not been elucidated, but a defective cytokine response may be involved. Therefore, we investigated whether an imbalance between IFNgamma and IL-10 may play a role in this disorder. We assessed the cytokine production in whole-blood cultures from CMC patients using Candida albicans, lipopolysaccharide and phytohaemagglutinin as stimuli. As the Toll-like receptors are important pattern recognition receptors for Candida species, we also investigated Toll-like receptor polymorphisms in these patients. Patients with CMC had a significantly decreased IFNgamma production when whole blood was stimulated with C. albicans (232 +/- 120 vs 2279 +/- 609 pg/ml, p<0.02). When stimulated with phytohaemagglutinin, the differences were not significant (3549 +/- 1320 vs 7631 +/- 1790 pg/ml). The Candida-stimulated production of IL-10 tended to be higher in CMC patients, whereas TNF and IL-1beta production were similar in patients and controls. Stimulation with LPS showed no differences in cytokine production between patients and controls. Two out of seven patients had the TLR4 Asp299Gly polymorphism and none had the TLR2 Arg677Trp polymorphism. These data support the hypothesis that deficient IFNgamma production is involved in the pathogenesis of CMC, whereas a role for genetic polymorphisms of Toll-like receptor 2 and 4 is not obvious in these patients.     

Toll样受体4的信号转导与溃疡性结肠炎的研究进展

溃疡性结肠炎(ulcerative colitis, UC)的发病机制尚不明确,目前研究表明,Toll样受体4(Toll-like receptor 4,TLR4)与UC的发病密切相关,TLR4通过髓样分化因子88 (myeloid differentiation factor 88, MyD88)依赖性和非依赖性等途径激活下游信号分子,引发肠黏膜释放TNF-α、IL-1、IL-6等炎症介质,最终导致UC的发生,同时对此信号转导通路的阻断研究为临床治疗UC带来了新的契机.     

Ticlopidine does not reduce in vivo platelet thromboxane biosynthesis and metabolism in diabetic patients

Diabetic patients are at higher risk of development of cardiovascular complications than the general population. The role of platelets in the pathogenesis of these complications is still controversial, it being difficult to ascertain whether altered platelet function is a cause or consequence of vascular complications of diabetes. Measurement of urinary 11-dehydro-thromboxane has been proposed as a reliable index of in vivo platelet activation and has been reported to be significantly higher in non insulin-dependent diabetic patients with micro- or macrovascular complications. We therefore studied the effect of ticlopidine, an antiplatelet drug acting through mechanisms different from cyclo-oxygenase inhibition, on urinary 11-dehydro-TXB(2) excretion in diabetic patients with macrovascular complications. The results indicate that urinary excretion of 11-dehydro-TXB(2) after ticlopidine treatment is not different from pre-treatment values, suggesting that the chosen parameter might not be reliable for monitoring the antiplatelet activity of ticlopidine and possibly of other drugs which do not directly affect arachidonic acid metabolism.     

Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections

Human toll-like receptor 4 (hTLR4) and CD14 are known to be components of the lipopolysaccharide receptor complex. Our study investigated the association between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphism(s) with outcome in an intensive care unit (ICU) population at risk for sepsis. By use of a polymerase chain reaction-based restriction fragment-length polymorphism analysis technique, the hTLR4 gene was altered in 14 (18%) of 77 ICU patients (all positive for systemic inflammatory response syndrome) and in 5 (13%) of 39 volunteers. There was a significantly higher incidence of gram-negative infection among patients with the mutations (11 [79%] of 14), compared with that in the wild-type population (11 [17%] of 63; P=.004). No association between CD14 polymorphism(s) and the incidence of infection or outcome was observed. These findings indicate that hTLR4 mutations are associated with an increased incidence of gram-negative infections in critically ill patients in a surgical setting.     

Increased in vivo biosynthesis of prostacyclin and thromboxane A2 in chronic idiopathic thrombocytopenic purpura

The production of thromboxane A2 (TxA2) and prostacyclin (PGI2) was studied in patients with chronic idiopathic thrombocytopenic purpura (10 patients) compared to central thrombocytopenia (five patients) and healthy subjects (10 subjects). This production was monitored by the assay of urinary 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha as respective breakdown products of TxA2 and PGI2 by stable isotope dilution assays employing negative ion-chemical gas-chromatography-mass-spectrometry. Evidence is presented for the existence of an enhanced PGI2 and TxA2 urinary excretion in the group of idiopathic thrombocytopenic purpura (ITP) patients. Moreover, production of serum TxB2 per platelet was decreased in ITP group. These results provide arguments for an in vivo platelet cyclooxygenase hyperactivity during chronic ITP.     

Demonstration of increased toll-like receptor 2 and toll-like receptor 4 expression in monocytes of type 1 diabetes mellitus patients with microvascular complications

Type 1 diabetes mellitus (T1DM) is associated with increased microvascular complications and is a proinflammatory state. The toll-like receptors (TLRs) are pattern recognition receptors on monocytes and important in atherosclerosis. We have shown increased TLR2 and TLR4 expression on monocytes of T1DM compared with controls. In this report, we tested the surface expression of TLR2 and TLR4 on monocytes of T1DM patients with microvascular complications (T1DM-MV) compared with those without (T1DM) and healthy controls. The study was performed at the University of California Davis. Healthy controls (n = 31), T1DM patients (n = 31), and T1DM-MV patients (n = 34) were included. The TLR2 and TLR4 surface expression was significantly increased in T1DM-MV monocytes compared with T1DM and controls (P < .01). In addition, nuclear factor κB activity and interleukin-1β release were significantly increased in monocytes from T1DM-MV compared with T1DM (P < .005). Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM-MV compared with T1DM and may contribute to the accentuated proinflammatory state and complications of T1DM.     

Toll样受体4在D-氨基半乳糖/内毒素介导的急性肝损伤中的表达

目的研究D-氨基半乳糖(D-Gal)/内毒素介导的急性肝损伤模型中肝组织细胞Toll样受体4(TLR4)的表达变化,探讨TLR4在识别内毒素、启动炎性肝损伤中的作用.方法 BALB/C小鼠腹内注射D-Gal 900 mg/kg与内毒素(即脂多糖,LPS)10 μg/kg后0～7 h分别检测血清丙氨酸转氨酶(ALT)及天门冬氨酸转氨酶(AST)与血浆肿瘤坏死因子(TNF-α)含量以评价肝功能;另随机取10只小鼠给药后观察致死率.用半定量逆转录-聚合酶链反应(RT-PCR)和Tanon Gis 2.0软件分析不同时间点肝组织中TLR4 mRNA表达,并与血浆TNF-α含量进行相关分析;免疫组织化学观察肝组织TLR4蛋白的表达.实验数据用SAS软件分析.结果给药后4 h,血清转氨酶明显升高(与0h比较,P＜0.05);血浆TNF-α含量逐步上升,在2 h、5 h有两个分泌高峰;7 h小鼠开始死亡,10 h致死率达80%.正常小鼠肝组织少量表达TLR4 mRNA,给药后表达明显增强(与0 h比较,P＜0.05);免疫组织化学也显示TLR4蛋白有类似的变化,尤其肝窦内皮细胞、库普弗细胞表达更为显著.血浆TNF-α含量与肝组织TLR4 mRNA表达呈正相关.结论肝内细胞膜上表达的TLR4可能通过启动下游的炎性应答基因表达及细胞因子释放而诱导出肝组织对LPS的炎性应答.因此,调控TLR4表达可能是感染性疾病防治的一种新策略.     

Toll样受体4介导的Th2免疫在支气管哮喘中的作用

支气管哮喘(简称哮喘)是一种以Th2优势免疫为特征的慢性气道炎症性疾病.Toll样受体4(TLR4)是表达在固有免疫细胞表面的模式识别受体,与病原体相关分子模式结合并启动细胞内信号转导.脂多糖介导的TLR4信号转导激活核转录因子NF-κB,引起固有免疫细胞活化.一方面,分泌多种促炎症细胞因子、参与炎症形成,并促进抗原递...     

Association between thromboxane A2 receptor polymorphisms and asthma risk: A meta-analysis

Objective: To determine whether there is an association between thromboxane A2 receptor (TBXA2R) gene polymorphisms (+924C/T and +795C/T) and asthma risk by conducting a meta-analysis. Data Sources: Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang database were searched (updated May 1, 2015). Study Selections: Articles evaluating the association between TBXA2R gene polymorphisms and asthma risk were selected. Results: A total of 7 studies on +924C/T polymorphism and 6 studies on +795C/T polymorphism were included in this meta-analysis. There was a significant association between TBXA2R +924C/T polymorphism and asthma risk in the recessive model (OR = 1.33, 95% CI = 1.01–1.75, P = 0.045). No significant association between +795C/T polymorphism and asthma risk in the overall population was demonstrated. In subgroup analyzes, significant association was observed in atopic asthma risk in the recessive model (OR = 1.43, 95% CI = 1.01–2.01, P = 0.043), but no significant association was found between TBXA2R +924C/T polymorphism and asthma risk in Asians (OR = 1.14, 95% CI = 0.80–1.63, P = 0.457). TBXA2R +795C/T polymorphism was associated with aspirin-intolerant asthma (AIA) risk when stratified by asthma subphenotype in the allelic model (OR = 1.30, 95% CI = 1.05–1.60, P = 0.014) and dominant model (OR = 1.50, 95% CI = 1.11–2.03, P = 0.008). Conclusion: Our results suggested that TBXA2R +924C/T polymorphism is associated with asthma risk, and +795C/T polymorphism may be a risk factor for AIA. Larger-scale and well-designed studies are required to validate the association identified in the current meta-analysis.