Significant role of IL-1 signaling, but limited role of inflammasome activation, in oviduct pathology during Chlamydia muridarum genital infection

IL-1β has been implicated in the development of oviduct pathology during Chlamydia muridarum genital infection in the mouse model. The goal of this study was to characterize the role of IL-1 signaling and the inflammasome-activation pathways during genital chlamydial infection. Compared with control mice, IL-1R-deficient mice displayed delayed clearance and increased chlamydial colonization. Consistent with the role for IL-1 signaling in infection clearance, mice deficient for the IL-1R antagonist cleared infection at a faster rate. Despite increased infection, IL-1R-deficient mice had significantly reduced oviduct pathology, which was associated with decreased numbers of neutrophils, but more macrophages, in the genital tract. IL-1β secretion is dependent on caspase-1 and apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) inflammasome during in vitro infection of primed macrophages with C. muridarum. To investigate the role of inflammasome components during in vivo genital infection, mice lacking NLRP3, NLRC4, and ASC were tested and found to display no reduction in oviduct pathology compared with control mice. Mice deficient for ASC displayed a prolonged course of infection, which was associated with reduced T cell recruitment and proliferation. Further, ASC-deficient mice displayed normal levels of IL-1β in genital secretions. However, a significant decrease in caspase-1-dependent IL-18 was observed in both ASC- and NLRP3-deficient mice. These data demonstrate a major role for IL-1 signaling, but a limited role for the inflammasome pathway, in IL-1β secretion and development of oviduct pathology during genital chlamydial infection. The data also suggest an IL-1-independent role for ASC in adaptive immunity during genital chlamydial infection.     

肺炎嗜衣原体、IL-6与冠心病关系的血清学探讨

采用血清学的方法观察冠心病(CHD)与肺炎嗜衣原体感染及白细胞介素-6之间相关性并对其致病机理作一简要探讨。用酶联免疫吸附分析(ELISA)技术检测136例CHD患者血清中的肺炎嗜衣原体抗体CP-IgA、CP-IgG、CP-IgM阳性率,并对其中肺炎嗜衣原体阳性者进行IL-6的检测。有64%CHD患者血清特异性CP-IgA呈阳性,与健康对照组的8.8%阳性率差异显著(P<0.01);而CP-IgG和CP-IgM与对照组的阳性率无显著差异(P>0.05);CHD肺炎嗜衣原体CP-IgA阳性者的IL-6明显高于对照组,两者之间有显著的差异(P<0.01)。冠心病病人血清肺炎嗜衣原体抗IgA的高阳性率与冠心病之间存在着有意义的联系,是CP-IgA慢性感染CP的标记物,肺炎嗜衣原体感染参与了冠心病的发生与发展。而炎症因子IL-6水平的升高也提示炎症反应在冠心病的发生以及疾病的发展过程中起着重要的作用。     

应用椭偏光学显微成像对IL-6与其受体的相互应用的初步观察

白细胞介素 6 (ＩＬ 6 )是一种具有复杂生物功能的细胞因子 ,可由多种淋巴类和非淋巴类细胞产生。它对机体多种组织及细胞均有不同程度的作用[1～ 3 ] 。近年来发现 ,临床上免疫异常性疾病 ,如发热、淋巴结肿大、血沉增快、急性期蛋白增高、高γ球蛋白血症、自身抗体阳性等症状都与ＩＬ 6的异常表达密切相关。ＩＬ 6的生物活性是通过细胞膜表面特异性受体介导的[4] 。研究ＩＬ 6与其受体的相互作用对于揭示某些疾病的发病机制 ,监测疾病进程以及指导临床治疗等均具有重要意义。用于研究ＩＬ 6与其受体相互作用的方法主要有ＩＬ 6依赖株细胞…     

沙眼衣原体持续感染对Hela细胞TLR4/IL-6/STAT3信号通路的影响

目的：分析沙眼衣原体（Chlamydia trachomatis,Ct）持续感染对靶细胞TLR4/IL-6/STAT3信号通路的影响.方法：利用Hela细胞分别建立Ct急性感染及持续性感染模型,通过qRT-PCR、ELISA等方法比较Ct感染过程中靶细胞TLR4、STAT3、IL-6转录水平及细胞因子IL-6分泌量的变化.结果：Ct感染后靶细胞TLR4、IL-6、STAT3转录水平及细胞因子IL-6分泌量均呈现时间相关性上调,且持续性感染状态下比急性感染状态下的上调更为显著;IL-6/STAT3的表达量与TLR4转录水平正相关.结论：Ct持续感染过程中TLR4 的持续活化可大幅上调IL-6/STAT3信号通路表达,可能参与了Ct持续感染后慢性炎性损伤过程.     

IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspectives

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD). Interleukin-6 (IL-6) signaling participates in inflammation responses central to the progression of DN. Current evidence suggests that these IL-6 responses are mediated via gp130–STAT3 dependent mechanisms which, on one hand, trigger globally the transition from innate to adaptive immune response, and on the other hand act locally for tissue remodeling and immune cell infiltration. In diabetic conditions the role of IL-6 is not well elucidated. Both IL-6 classical signaling pathway via receptor IL-6R (IL-6R) and IL-6 trans-signaling pathway via soluble IL-6R (sIL-6R) were shown to participate in the pathogenesis and progression of DN, and IL-6 appears to influence renal cells also in an autocrine manner. To date, evidence is limited. The goal of this review is to provide an overview of our current understanding on the role of IL-6 signaling in DN and to delineate challenges for future research. Putative sequential events related to IL-6 secretion by different cell populations in diabetic conditions are outlined. Further, we discuss potential applications of anti-IL-6 therapy in the context of DN.     

The involvement of IL-6 and IL-8 in acute invasive gastroenteritis of children

The involvement of the proinflammatory cytokines, interleukin 8 (IL-8) and 6 (IL-6), was studied during the first 72 h of acute invasive gastroenteritis. Study population included 33 infants and young children aged six months to six years and seven age-matched controls. As a group, patients with acute invasive gastroenteritis had an increased serum level of IL-8 and IL-6 as compared with healthy controls (p < 0.002 and p < 0.001, respectively). Subjects were then divided into two groups based on stool cultures (proven and non-proven bacterial cultures). Patients with bacterial-proven acute invasive gastroenteritis tended to have increased IL-8 serum concentrations (p < 0.07) as compared with those with non-proven bacterial etiologies and IL-6 levels were only detected in subjects with positive bacterial cultures (p < 0.05). When dividing each sub-group into early and late blood drawing with respect to disease onset, no statistical differences were found in each group but subjects with bacterial-proven etiologies had significant higher IL-6 levels as compared with non-proven etiologies at the two time points (p < 0.019 and p < 0.015, respectively).In conclusion, the proinflammatory cytokines, IL-6 and IL-8, are involved in acute invasive gastroenteritis. The difference in IL-6, and to a lesser degree IL-8, between proven and non-proven bacterial etiologies, needs further investigation.     

冠心病患者血清IL-37水平及其与血清IL-6、IL-10、CRP水平的关系

目的:探讨不同类型冠心病患者血清白介素-37(IL-37)的水平及其与血清白介素-6(IL-6)、白介素-10(IL-10)、C反应蛋白(CRP)水平的关系。方法:选取急性心肌梗死患者20例(AMI组)、不稳定性心绞痛患者26例(UAP组)、稳定性心绞痛患者20例(SAP组)及冠脉造影正常者26例(CON组)为研究对象,采用酶联免疫吸附法(ELISA)测定其血清IL-37、IL-6、IL-10和CRP的水平并分析其相关性。结果:1UAP组、AMI组血清IL-37水平均较对照组(CON组)显著增高(p0.05),而SAP组与CON组比较无明显差异(P0.05)。2冠心病患者的血清IL-37水平与其血清CRP(r=0.3,P0.05)、IL-6(r=0.4,P0.05)水平均存在显著正相关性,与IL-10水平无明显相关(P=0.16)。当排除SAP组患者后,冠心病患者的血清IL-37水平与CRP(r=0.3,P0.05)、IL-6(r=0.5,P0.05)、IL-10(r=0.2,P0.05)水平均显著相关。结论:急性冠脉综合症(ACS)患者的血清IL-37水平显著升高,并与IL-6、IL-10、CRP水平相关,可能参与了ACS发病过程中的炎症反应。     

人IL-6受体胞外区真核表达载体的构建及体外表达

目的构建人IL-6受体（IL-6R）胞外区真核表达载体,检测其在体外培养细胞中的表达。方法利用PCR扩增IL-6R胞外区,克隆到pcDNA3．1（＋）中,用双酶切、测序鉴定。重组质粒通过脂质体转染HL-60细胞,用G418进行筛选,利用Western印迹检测IL-6R蛋白表达。结果PCR扩增出1218bp的目的片段,双酶切和测序结果显示重组质粒正确。Western印迹结果显示转染细胞能够表达目的蛋白。结论成功构建了人IL-6R胞外区真核表达载体,并且能够在真核细胞中表达。     

白介素6的信号转导及其相关疾病的治疗策略

IL-6是一种多功能的细胞因子, 同时IL-6的过度表达与一些疾病的发生和发展有密切关系.IL-6通过一个双链受体系统作用于靶细胞.实验结果表明,IL-6与80 ku的配基结合链IL-6R和信号转导子gp130构成一个相互作用的异六聚体模式,通过gp130的二聚体化引发胞内的信号转导.IL-6胞内的信号转导途径有两种:Jak-STATs路径和Ras-MAPK级联反应路径.靶向IL-6信号转导的药物设计和筛选研究将为IL-6相关疾病的治疗奠定坚实的基础.     

IL-6与肿瘤耐药相关性的研究进展

【摘 要】 肿瘤对化疗药物耐药性的产生是造成治疗失败的主要因素。形成肿瘤耐药的机制很复杂。IL-6作为一种重要的炎性细胞因子与恶性肿瘤细胞对化疗药物耐药性密切相关。IL-6极有可能成为逆转某些恶性肿瘤耐药性的新靶点。     

降钙素原、IL-6及CRP诊断新生儿宫内细菌感染的临床价值

目的:探讨降钙素原、IL-6及CRP对新生儿宫内细菌感染诊断的临床价值。方法:采用回顾性分析方法,对121例疑似宫内细菌感染的新生儿的相关临床资料进行比较分析。通过影像学或细菌学方法对患儿进行检查判定感染类型,并检测患儿脐血中的降钙素原、C-反应蛋白(CRP)和白细胞介素-6(IL-6)的水平。结果:在121例患儿中41例确定为细菌感染,IL-6(100ng/L)与CRP(10mg/L)联合对诊断新生儿宫内细菌感染的敏感性为90.1%,特异性为76.9%,阴性预测率为91.7%,阳性预测率为71.9%;与PCT结合后,诊断新生儿宫内细菌感染的敏感性升高至98.3%,特异性为67.8%,阴性预测率为99.2%,阳性预测率为57.0%。结论:脐血PCT可作为新生儿宫内细菌感染诊断的有效指标,可明显提高IL-6与CRP诊断新生儿宫内细菌感染的阴性预测值和敏感性,指导临床治疗。     

TNF-alpha、IL-6及IL-8在不同程度溃疡性结肠炎患者血清中的表达及意义

目的：探讨不同严重程度溃疡性结肠炎患者血清TNF-alpha、IL-6 及IL-8 的表达及意义。方法：选择2011 年1 月~2014 年7 月 我院收治的溃疡性结肠炎患者47 例,根据严重程度将患者分为轻度组、中度组和重度组。另选取同期在我院接受健康体检的志 愿者80 例作为对照组。采用酶联免疫吸附试验（ELISA）检测各组患者血清TNF-alpha、IL-6 及IL-8 的水平。结果：溃疡性结肠炎患者 血清TNF-琢、IL-6 及IL-8 水平高于对照组,差异有统计学意义（P<0.05）;不同严重程度溃疡性结肠炎患者的TNF-alpha、IL-6 及IL-8 水平呈显著差异（P<0.05）。结论：检测溃疡性结肠炎患者血清TNF-alpha、IL-6 及IL-8的水平变化有利于预测病情进展。     

Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

The IL-6 signaling complex is described as a hexamer, formed by the association of two IL-6·IL-6 receptor (IL-6R)·gp130 trimers, with gp130 being the signal transducer inducing cis- and trans-mediated signaling via a membrane-bound or soluble form of the IL-6R, respectively. 25F10 is an anti-mouse IL-6R mAb that binds to both membrane-bound IL-6R and soluble IL-6R with the unique property of specifically inhibiting trans-mediated signaling events. In this study, epitope mapping revealed that 25F10 interacts at site IIb of IL-6R but allows the binding of IL-6 to the IL-6R and the recruitment of gp130, forming a trimer complex. Binding of 25F10 to IL-6R prevented the formation of the hexameric complex obligate for trans-mediated signaling, suggesting that the cis- and trans-modes of IL-6 signaling adopt different mechanisms for receptor complex assembly. To study this phenomenon also in the human system, we developed NI-1201, a mAb that targets, in the human IL-6R sequence, the epitope recognized by 25F10 for mice. Interestingly, NI-1201, however, did not selectively inhibit human IL-6 trans-signaling, although both mAbs produced beneficial outcomes in conditions of exacerbated IL-6 as compared with a site I-directed mAb. These findings shed light on the complexity of IL-6 signaling. First, triggering cis- versus trans-mediated IL-6 signaling occurs via distinctive mechanisms for receptor complex assembly in mice. Second, the formation of the receptor complex leading to cis- and trans-signaling biology in mice and humans is different, and this should be taken into account when developing strategies to inhibit IL-6 clinically.     

IL-6 and its role in IgA nephropathy development

IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes.Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria.This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.     

Role of IL-6 in Asthma and Other Inflammatory Pulmonary Diseases

The incidence and severity of chronic lung diseases is growing and affects between 100 and 150 million people worldwide and is associated with a significant rate of mortality. Unfortunately, the initial cause that triggers most chronic lung diseases remains unknown and current available therapies only ameliorate, but do not cure the disease. Thus, there is a need for identification of new targets and development of novel therapies especially for those most severely affected. IL-6, like other inflammatory cytokines, has been shown to be elevated in different lung diseases, but it was considered a byproduct of ongoing inflammation in the lung. However, recent studies support a dissociation of IL-6 from inflammation in the lung and suggest that this cytokine plays an active role in pathogenesis of asthma and, in all likelihood, COPD. IL-6 may therefore be a germane target for treatment of these and other chronic lung disease. Here, we provide an overview of the studies in mouse models and human patients that provide support for the involvement of IL-6 in lung diseases.     

糖皮质激素对大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8水平的影响

目的：探究糖皮质激素对大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8 水平的影响。方法：选取2014 年3 月至2014 年8月我院收 治的大叶性肺炎患儿60 例,并将其随机分为对照组和实验组。对照组30 例,给抗炎、退热、镇咳、平喘等临床常规治疗;实验组30 例,在与对照组相同治疗的基础上加用糖皮质激素联合治疗。治疗结束后,比较两组患儿治疗前后血清TNF-alpha、IL-6、IL-8 水平的 变化。结果：治疗前,两组患儿的血清TNF-alpha、IL-6、IL-8 水平比较均无统计学差异(P 均>0.05);治疗后,两组患儿的血清TNF- alpha、 IL-6、IL-8 水平均较治疗前显著降低(P 均<0.05),且实验组患儿的血清TNF-alpha、IL-6、IL-8 水平均显著低于对照组,差异均有统计 学意义(P 均<0.05)。结论：糖皮质激素辅助治疗可降低大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8 的水平,这可能是其治疗儿童大叶 性肺炎的药理学作用之一。