Melatonin attenuates methamphetamine‐induced overexpression of pro‐inflammatory cytokines in microglial cell lines

Abstract: Methamphetamine (METH), the most commonly abused drug, has long been known to induce neurotoxicity. METH causes oxidative stress and inflammation, as well as the overproduction of both reactive oxygen species (ROS) and reactive nitrogen species (RNS). The role of METH‐induced brain inflammation remains unclear. Imbroglio activation contributes to the neuronal damage that accompanies injury, disease and inflammation. METH may activate microglia to produce neuroinflammatory molecules. In highly aggressively proliferating immortalized (HAPI) cells, a rat microglial cell line, METH reduced cell viability in a concentration‐ and time‐dependent manner and initiated the expression of interleukin 1β (IL‐1β), interleukin 6 (IL‐6) and tumor necrosis factor α. METH also induced the production of both ROS and RNS in microglial cells. Pretreatment with melatonin, a major secretory product of the pineal gland, abolished METH‐induced toxicity, suppressed ROS and RNS formation and also had an inhibitory effect on cytotoxic factor gene expression. The expression of cytotoxic factors produced by microglia may contribute to central nervous system degeneration in amphetamine abusers. Melatonin attenuates METH toxicity and inhibits the expression of cytotoxic factor genes associated with ROS and RNS neutralization in HAPI microglia. Thus, melatonin might be one of the neuroprotective agents induced by METH toxicity and/or other immunogens.     

Significant association between toll‐like receptor gene polymorphisms and gallbladder cancer

Background: Toll‐like receptors (TLRs) are evolutionarily conserved cell surface receptors of innate immune system. Various polymorphisms in TLR genes have been identified and associated with susceptibility toward various malignancies such as prostate cancer, gastric cancer and colorectal cancer. The present study was undertaken to examine the potential association of two polymorphisms in TLR2 and TLR4 genes with gallbladder cancer (GBC) susceptibility. Methods: Genotypes and allelic frequencies of TLR2 and TLR4 gene polymorphisms were determined for 233 GBC patients and 257 cancer‐free controls randomly selected from the population, using polymerase chain reaction–restriction fragment length polymorphism. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in a multivariate logistic regression analysis for the association of TLR polymorphisms with GBC. Results: ‘del’ allele carriers of TLR2 (Δ22) polymorphism were associated with a 1.54‐fold increased risk for GBC (95% CI=1.02–2.24; P_trend=0.091). The TLR4 Ex4+936C >T polymorphism (g.14143C>T; rs4986791) was also found to be significantly associated with the overall higher risk of GBC under a dominant mode of inheritance (OR=1.96; 95% CI=1.11–2.26; P_trend=0.021). The false‐positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP<0.5). Subgroup analysis showed that TLR4 Ex4+936C>T polymorphism was associated with an increased risk of GBC in females and GBC cases with gallstones (OR=2.85 and 2.22 respectively). Conclusion: In summary, low‐penetrance variants in TLR genes may alter the susceptibility towards gallbladder cancer.     

Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation

L. Zhou, B. Wei, C. Xing, H. Xie, X. Yu, L. Wu, S. Zheng. Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation
Transpl Infect Dis 2011: 13: 250–258. All rights reserved Background Hepatitis B virus (HBV) recurrence is one of the more severe complications following liver transplantation. Toll‐like receptors (TLRs) play a key role in human immunity by recognizing various bacteria, viruses, fungi, and parasites. Single nucleotide polymorphisms (SNPs) in the TLRs are thought to have an impact on the susceptibility to some pathogens. This study focused on the association between polymorphisms in the TLRs and HBV recurrence after liver transplantation in Han Chinese patients. Methods. A total of 41 tag SNPs in TLRs were detected by the snapshot technique in 125 patients with primary HBV‐related diseases receiving liver transplantation in our center from 2004 to 2008. Results. By comparing the genetic variations and clinical data between the HBV recurrence patients and nonrecurrence patients, we found that the variant genotype of rs11536889 (TLR4) was significantly associated with HBV recurrence after liver transplantation (P=0.040, odds ratio was 0.390, 95% confidence interval 0.159–0.957). Conclusion. Our findings indicate that polymorphism in 3′‐untranslated regions of the TLR4 gene may be related to protection from HBV recurrence after liver transplantation in Han Chinese patients.     

Tamoxifen alleviates hepatitis C virus‐induced inhibition of both toll‐like receptor 7 and JAK‐STAT signalling pathways in PBMCs of infected Egyptian females

Summary. Hepatitis C virus (HCV) is a major health concern in Egypt being highly prevalent among Egyptians. The two genders experience different responses to HCV infection and show variations in response to interferon (IFN)‐based therapy that may be attributed to sex hormones. We previously demonstrated the suppressive effect of 17β‐estradiol (E2) on the expression of the IFN‐stimulated gene MxA in HCV‐infected peripheral blood mononuclear cells (PBMCs). The selective oestrogen receptor (ER) modulator Tamoxifen has been shown to have an antiviral effect against HCV, but its effect on the host immune response is unknown. We investigated the effect of Tamoxifen on the IFN signalling pathways in PBMCs of HCV‐infected Egyptian females. We pooled PBMCs and treated then with exogenous interferon alpha (IFNα) or the TLR7 ligand, Imiquimod, and quantified the relative expressions of MxA using RTqPCR. Studies were performed with and without Tamoxifen pretreatment. Pretreatment with Tamoxifen reversed the suppressive effect of E2 on the JAK‐STAT pathway in IFNα‐treated PBMCs as indicated by a significant increase in MxA expression (P = 0.05*). Tamoxifen pretreatment also significantly upregulated MxA expression in Imiquimod‐treated PBMCs (P = 0.0011**), an effect not ascribed to ER blocking nor to an upregulation in TLR7 expression because Tamoxifen showed no potentiating effect on the expression of the receptor. In conclusion, our findings reveal that Tamoxifen has immunomodulatory effects whereby it enhances the host IFN signalling pathways during HCV infection.     

Monocytes from children with clinically stable cystic fibrosis show enhanced expression of Toll‐like receptor 4

Lung disease in patients with cystic fibrosis (CF) is characterized by recurrent bacterial respiratory infections and intense airway inflammation. Pattern recognition receptors such as Toll‐like receptor 2 (TLR2) and TLR4 identify bacterial pathogens and activate the innate immune response. We therefore hypothesized that increased expression of these receptors would be found on circulating immune cells from children with CF. A cohort of 66 young children (median age 3 years) with CF was studied and compared to both healthy controls (n = 14) and children without CF who were being investigated for recurrent respiratory infections (non‐CF disease controls; n = 17) of a similar age. Surface expression of TLR2 and TLR4 on peripheral blood monocytes was analyzed using flow cytometry. TLR4 expression was significantly higher in patients with CF compared to healthy controls (P = 0.017) and non‐CF disease controls (P = 0.025) but did not vary according to the presence or absence of pulmonary infection with Gram‐negative or Gram‐positive bacteria (P = 0.387) in the CF group. In contrast, TLR2 expression was similar across all three study groups (P = 0.930). The increased surface expression of TLR4 seen in young children with CF appears to be related to having CF per se and not related to current pulmonary infection. Pediatr. Pulmonol. © 2010 Wiley‐Liss, Inc.     

Regulation of high‐density lipoprotein by inflammatory cytokines: establishing links between immune dysfunction and cardiovascular disease

Coronary artery disease is a primary co‐morbidity in metabolic diseases such as metabolic syndrome, diabetes and obesity. One contributing risk factor for coronary artery disease is low high‐density lipoprotein‐cholesterol (HDLc). Several factors influence steady‐state HDLc levels, including diet, genetics and environment. Perhaps more important to coronary artery disease is factors that attribute to the dynamics of reverse cholesterol transport, storage, and excretion of excess cholesterol. HDLc biogenesis, clearance and innate ability to serve as a cholesterol acceptor and transporter all contribute to HDLc's function as a negative regulator of cardiovascular disease. With the recent failure of torcetrapid, focus is being placed on HDLc biology and its role in various metabolic diseases. Low HDLc levels are often associated with an increased state of background inflammation. Recently, several syndromes with clear pro‐inflammatory components have been shown to be inversely correlated with low HDLc levels in the absence of obesity, diabetes and metabolic syndrome. Early studies with HDLc during the acute‐phase response suggest that HDLc is substantially physically modified during acute infection and sepsis, and recent studies show that HDLc is physically modified by chronic pro‐inflammatory disease. In this review, several of these connections are described and cytokine signalling related to HDLc is examined. Copyright © 2010 John Wiley & Sons, Ltd.     

急性心肌梗死患者溶栓前后外周血单个核细胞Toll样受体4的变化

目的:比较急性心肌梗死(AMI)患者溶栓前、后再通组与未通组外周血单个核细胞(PBMCs)上Toll样受体4(TLR4)的表达变化,探讨其在心肌缺血/再灌注损伤(MI/RI)炎症反应中的作用.方法:72例AMI患者溶栓治疗后分为溶栓再通组(43例)与未通组(29例),所有患者均于溶栓前,溶栓后2、6、12、24 h分别采肘静脉血8 ml,肝素抗凝.健康体检者40例作为正常对照组.流式细胞术测定外周血TLR4蛋白的表达,实时荧光定量PCR和酶联免疫吸附法(ELISA)分别检测外周血PBMCs上TLR4 mRNA、髓样分化蛋白88(Myd88)mRNA的表达和血浆中肿瘤坏死因子-α(TNF-α)的浓度.结果:溶栓前以上各指标比较差异均无统计学意义(P>0.05),但均高于正常对照组各指标水平(P<0.01).溶栓后,其表达水平均有所上调,达峰值后,又有所下降.与未通组比较,再通组上述各指标达峰时间均提前,且峰值水平较低,同时下降迅速.无论溶栓再通与否,TLR4 mRNA与Myd88 mRNA均呈正相关,其中相关系数分别为0.886,0.694(P<0.01).结论:AMI患者持续的缺血或成功的再灌注后外周血PBMCs上TLR4表达上调,TLR4可能通过Myd88依赖性的信号转导通路促进TNF-α分泌,介导MI/RI的炎症反应.