哺乳动物Toll样受体对结核分枝杆菌的控制

针对胞内菌结核分枝杆菌最为有效的免疫应答主要取决于天然免疫应答对侵入细菌的早期发现及获得性免疫应答的活化。Toll样受体在天然免疫应答发现分枝杆菌相关性分子和介导抗菌效应分子的分泌上起作用。它能调节一些免疫调节分子,这些分子能促进基于Th1细胞的T细胞发育。因此,Toll样受体的活化在抗微生物感染的机制上起一定的作用。     

Toll样受体的研究进展

Toll样受体是近几年发现的天然免疫受体,它们不仅能特异性地识别病原微生物的结构成分,激活天然免疫,同时也为激活获得性免疫提供共刺激信号。Toll样受体是天然免疫与获得性免疫之间的连接点。     

Toll 样受体与天然免疫

Toll样受体家族是一类模式识别受体,它介导了一个植物,昆虫,哺乳动物共同拥有的高度保守的信号通路。最近几年相继发现了多种人类Toll样受体以及相关的病原微生物配体,这些配体涵盖了病毒,细菌,真菌等微生物上多种保守的病原相关分子模式。可见Toll样受体在多种病原微生物及其产物的识别和免疫防御反应中有重要的作用。     

Toll样受体家族与天然免疫

Toll受体是近年来发现的跨膜信号传递受体蛋白,它在哺乳动物,昆虫及植物的信号转导通路中有类似的作用。TLR可选择性识别病原微生物而启动天然免疫,因此,它在宿主的天然免疫中具有重要作用。本文主要对TLR家族的研究进展及其在天然免疫中的作用加以综述。     

Toll 样受体研究进展

Toll样受体（Toll－like receptors,TLRs）是新近发现的先天性免疫系统中的细胞跨膜受体及病原模式识别受体之一,在急性炎症反应细胞吞噬作用的调节和细胞信号转导及细胞凋亡中起重要作用,简要综述了Toll样受体的发现、分布、基因定位与结构特点、配体特异性及其介导的信号通路,并对其研究意义与前景作了简述。     

Toll样受体研究进展

Toll最早在果蝇中被发现。Toll受体蛋白（dToll）不仅参与果蝇胚胎发育时背腹的形成,而且参与成蝇对病原体侵袭的先天性免疫应答,是微生物诱导成年果蝇产生抗菌肽的信号转导通道的门户。Toll样受体是先天性模式识别受体,在细胞活化信号的转导中起重要作用。它作为联系先天性与获得性免疫系统的桥梁,备受人们关注。     

Toll样受体4与肝损伤的研究进展

Toll样受体4((toll like receptor4,TLR4)是内毒素(LPS)的关键受体,为Toll蛋白家族中的一个成员,是联系固有免疫和适应性免疫的纽带。TLR4主要表达于髓源性细胞,其启动的胞内信号转导在肝损伤的发生和发展过程中发挥重要作用。这一信号转导途径主要通过NF-κB、p38、JNK等的激活,使细胞产生炎症转录因子,介导肝脏炎症。TLR4与氧化应激的相互作用,使得肝脏对TLR4的配体及细胞因子的敏感性增加,从而加重肝脏损伤。随着TLR4在肝损伤中的作用进一步阐明,其在肝脏疾病中的治疗作用将会产生广阔的应用前景。     

Toll样受体的发现者——布特勒

先天性免疫是高等动物感知外界感染后迅速启动机体防御反应的一种方式,对该过程机制的理解在临床方面具有非常广泛的应用。布特勒先后发现了介导多种炎症反应的肿瘤坏死因子、感知脂多糖的Toll样受体4等物质,这些进展拓宽了人们对先天免疫分子机制认识同时也得到广泛临床应用,布特勒也被认为是近几年诺贝尔生理与医学奖的热门人选之一。     

Toll样受体及其信号转导

Toll样受体(TLR)介导着绝大部分哺乳动物、昆虫及植物的宿主防御. TLR4与配体结合涉及膜抗原CD14和分泌蛋白MD-2的调节并一起形成受体复合物, 然后与接头分子MyD88结合, 使IRAK磷酸化, 再使TRAF6寡聚化, 随后激活控制着各种效应基因表达的转录因子NF-κB.     

Toll样受体介导的肠道免疫研究进展

黏膜免疫系统的第一道防线——肠黏膜上皮,不但能区分和识别致病菌和共生菌,而且能启动适当的免疫应答。在机体正常情况下,肠黏膜上皮细胞（IEC）对肠道共生菌持耐受状态,维持肠道内环境的稳定。IEC能识别致病菌的危险信号,激活派伊尔结节,启动免疫应答。有关实验已证实肠黏膜上皮针对肠腔细菌呈“耐受”或“非耐受”状态,主要依赖于Toll样受体（TLRS）介导的信号转导通路。     

Innate responses of corneal epithelial cells against Aspergillus fumigatus challenge

Toll-like receptors (TLRs) are key components of the innate immune system that detects microbial infection and triggers host defensive responses. To determine the roles of TLR2 and TLR4 in corneal epithelial cells in mediating innate responses against Aspergillus fumigatus , telomerase-immortalized human corneal epithelial cells (THCE) were challenged by TLR2 ligand zymosan, TLR4 ligand lipopolysaccharide and A. fumigatus hyphae, respectively. Culture media were collected at different time points and enzyme-linked immunosorbent assay was performed to detect the levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-6. We found that THCE responded to the challenge of TLR2 or TLR4 ligand by expressing and secreting inflammatory cytokines into the culture media. And exposure of THCE to A. fumigatus hyphae resulted in the upregulation of IL-1β and IL-6. Treatment with TLR2- or TLR4-siRNA plasmid reduced TLR2 or TLR4 expression level in THCE when compared with controls, and caused a significant decrease in A. fumigatus -induced IL-1β and IL-6 production. Our results suggested that THCE can respond to TLR2 and TLR4 ligand challenge by secreting IL-1β and IL-6. They recognize A. fumigatus hyphae via TLR2 and TLR4 and initiate innate immune responses. Corneal epithelial cells play a role in innate defense against fungal infection through the mediation of inflammatory cytokines production.     

Synthesis and immunoregulatory activities of conjugates of a Toll-like receptor 7 inert ligand

In the synthesis and modification of the analogs of an adenine type of Toll-like receptor (TLR) 7 agonists, we found a special compound, 9-propionyloxy-8-hydroxy-2-(2-methoxyethoxy)-adenine (6). It is a synthesized TLR7 inert ligand, which does not respond to TLR7 itself. However, it can be coupled with protein or peptide antigens via propionyloxy functional group to promote their immunogenicity significantly. The compound was covalently coupled to protein and peptide to get the conjugates. The inductivity of cytokine production by the conjugates was 872.4-fold compared with the unconjugated antigens in vitro by mouse splenocyte. These data show that the immunostimulatory activity of inert TLR7 ligand can be endowed, and the activity of antigens can be amplified by conjugation with various proteins and peptides, thus broadening the potential therapeutic application and reducing the risk of TLR7 agonists’ side effects.     

Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Cannabinoid receptor type 2(CB2)activation is recently reported to promote proliferation of some types of resident stem cells(e.g.,hematopoietic stem/progenitor cell or neural progenitor cell).Resident cardiac progenitor cell(CPC)activation and proliferation are crucial for endogenous cardiac regeneration and cardiac repair after myocardial infarction(MI).This study aims to explore the role and possible mechanisms of CB2receptor activation in enhancing myocardial repair.Our results revealed that CB2receptor agonist AM1241 can significantly increase CPCs by c-kit and Runx1 staining in ischemic myocardium as well as improve cardiomyocyte proliferation.AM1241 also decreased serum levels of MDA,TNF-αand IL-6 after MI.In addition,AM1241 can ameliorate left ventricular ejection fraction and fractional shortening,and reduce fibrosis.Moreover,AM1241 treatment markedly increased p-Akt and HO-1 expression,and promoted Nrf-2 nuclear translocation.However,PI3K inhibitor wortmannin eliminated these cardioprotective roles of AM1241.In conclusion,AM1241 could induce myocardial regeneration and improve cardiac function,which might be associated with PI3K/Akt/Nrf2 signaling pathway activation.Our findings may provide a promising strategy for cardiac endogenous regeneration after MI.     

Adaptive inflammatory microenvironment for cell-based regeneration in ischemic cardiovascular disease

Cell-based therapy has emerged to be a promising strategy for alleviating the heavy burden of ischemic cardiovascular disease for nearly two decades, despite a variety of pending questions about its availability and efficacy. One question is whether and how the cells behave for regeneration in vivo, which could be limited or potentiated by the inflammatory microenvironment following myocardial infarction or critical limb ischemia. To this end, we hypothesize that the “adaptive inflammatory microenvironment” is pertinent to the cell-based regeneration, and make a brief comment on it based upon recent evidence.     

Identification of neuromedin S and its possible role in the mammalian circadian oscillator system

The discovery of neuropeptides has resulted in an increased understanding of novel regulatory mechanisms of certain physiological phenomena. Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan G protein-coupled receptor FM-4/TGR-1, which was identified to date as the neuromedin U (NMU) receptor, and designate this peptide 'neuromedin S (NMS)' because it is specifically expressed in the suprachiasmatic nuclei (SCN) of the hypothalamus. NMS shares a C-terminal core structure with NMU. The NMS precursor contains another novel peptide. NMS mRNA is highly expressed in the central nervous system, spleen and testis. In rat brain, NMS expression is restricted to the core of the SCN and has a diurnal peak under light/dark cycling, but remains stable under constant darkness. Intracerebroventricular administration of NMS in rats activates SCN neurons and induces nonphotic type phase shifts in the circadian rhythm of locomotor activity. These findings suggest that NMS in the SCN is implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions.