Toll样受体对病原真菌的天然免疫识别

天然免疫系统是宿主抵御病原入侵的第一道防线,在机体抗感染免疫中发挥重要作用。Toll样受体(Toll-like receptors,TLRs)是天然免疫系统最重要的模式识别受体(pattern recognitionreceptors,PRRs)之一,通过识别病原真菌的病原相关分子模式(pathogen-associated molecularpatterns,PAMPs),招募特异接头蛋白,激活一系列信号级联反应,引发炎症因子、趋化因子等的释放和树突状细胞(dendritic cells,DCs)的成熟,发挥抗真菌感染作用。通过简要介绍宿主的TLRs及信号通路的研究进展,总结了目前TLRs对不同病原真菌PAMPs的天然免疫识别及信号通路研究现状,以期对进一步研究宿主天然免疫系统与病原真菌相互作用的分子机制提供参考。     

Endotoxin recognition: in fish or not in fish?

The interaction between pathogens and their multicellular hosts is initiated by activation of pathogen recognition receptors (PRRs). These receptors, that include most notably members of the toll-like receptor (TLR) family, recognize specific pathogen-associated molecular patterns (PAMPs). TLR4 is a central part of the receptor complex that is involved in the activation of the immune system by lipopolysaccharide (LPS) through the specific recognition of its endotoxic moiety (Lipid A). This is a critical event that is essential for the immune response to Gram-negative bacteria as well as the etiology of endotoxic shock. Interestingly, compared to mammals, fish are resistant to endotoxic shock. This in vivo resistance concurs with in vitro studies demonstrating significantly lowered sensitivity of fish leukocytes to LPS activation. Further, our in vitro analyses demonstrate that in trout mononuclear phagocytes, LPS fails to induce antiviral genes, an event that occurs downstream of TLR4 and is required for the development of endotoxic shock. Finally, an in silico approach that includes mining of different piscine genomic and EST databases, reveals the presence in fish of all of the major TLR signaling elements except for the molecules specifically involved in TLR4-mediated endotoxin recognition and signaling in mammals. Collectively, our analysis questions the existence of TLR4-mediated cellular responses to LPS in fish. We further speculate that other receptors, in particular beta-2 integrins, may play a primary role in the activation of piscine leukocytes by LPS.     

Role of toll-like receptors gene polymorphism in hepatocellular carcinoma

Abstract

Toll-like receptors (TLRs), evolutionarily conserved innate, play important roles in the development of autoimmunity. TLRs proteins are localized on the cell surface or in endosomes and play critical roles in innate immune responses against different pathogens. Aberrant stimulation of the innate immune system through intracellular TLRs may lead to hyperactive immune responses and contribute to the pathogenesis of hepatocellular carcinoma (HCC). HCC is the seventh most common cancer and the third leading cause of cancer deaths worldwide, and innate immune takes a most important role in HCC. There was no review to sum up the role of TLRs gene polymorphism in HCC. This review was performed to sum up the role of TLRs gene polymorphism in HCC.     

Early pregnancy affects the expression of toll-like receptor pathway in ovine thymus

Toll-like receptors (TLRs) participates in regulation of the maternal immune tolerance during pregnancy, and the thymus is critical for the adaptive immune system. This study hypothesized whether early pregnancy affected the expression of toll-like receptor pathway in the thymus of ewes. In this study, expression of TLRs, tumor necrosis factor receptor associated factor 6 (TRAF6), interleukin 1 receptor associated kinase 1 (IRAK1) and myeloid differentiation primary response gene 88 (MyD88) was detected in maternal thymus during early pregnancy in sheep. Ovine thymuses were collected on day 16 of the estrous cycle, and days 13, 16 and 25 of pregnancy, and expression of TLR members was analyzed by real-time quantitative PCR, western blot and immunohistochemistry analysis. The results revealed that there were decreases in the expression of the mRNA and proteins of TLR2, IRAK1, TRAF6 and MyD88, but increase in TLR5 mRNA and protein. Furthermore, expression of TLR3 and TLR4 proteins peaked at days 13 and 16 of gestation, and MyD88 protein was located in the epithelial reticular cells and thymic corpuscles. In summary, TLR signaling is implicated in regulation of maternal thymic immune, which may be via downregulation of TLR2, IRAK1, TRAF6 and MyD88 during early pregnancy in sheep.     

Conservation and diversification of HAIRY MERISTEM gene family in land plants

The shoot apical meristems (SAMs) of land plants are crucial for plant growth and organ formation. In several angiosperms, the HAIRY MERISTEM (HAM) genes function as key regulators that control meristem development and stem cell homeostasis. To date, the origin and evolutionary history of the HAM family in land plants remains unclear. Potentially shared and divergent functions of HAM family members from angiosperms and non-angiosperms are also not known. In constructing a comprehensive phylogeny of the HAM family, we show that HAM proteins are widely present in land plants and that HAM proteins originated prior to the divergence of bryophytes. The HAM family was duplicated in a common ancestor of angiosperms, leading to two distinct groups: type I and type II. Type-II HAM members are widely present in angiosperms, whereas type-I HAM members were independently lost in different orders of monocots. Furthermore, HAM members from angiosperms and non-angiosperms (including bryophytes, lycophytes, ferns and gymnosperms) are able to replace the role of the type-II HAM genes in Arabidopsis, maintaining established SAMs and promoting the initiation of new stem cell niches. Our results uncover the conserved functions of HAM family members and reveal the conserved regulatory mechanisms underlying HAM expression patterning in meristems, providing insight into the evolution of key stem cell regulators in land plants.     

Accepted mutations in a gene family: Evolutionary diversification of duplicated DNA

Summary We report and compare the DNA sequences of 14 silkmoth (Antheraea polyphemus) chorion genes, derived from either cDNA or chromosomal DNA clones. Seven of these genes are members of the A multigene family, and seven are members of the B family. Where available, the previously reported (Jones and Kafatos 1980) intronic and extragenic flanking DNA sequences are also considered. Closely related sequences are compared, revealing the types of spontaneous mutations that were fixed during paralogous evolution. Segmental mutations (i.e. mutations other than substitutions) are nearly always interpretable as small duplications or deletions. related to small direct repeats. Segmental mutations are strongly constrained in the coding regions, although they do occur. Nucleotide substitutions also appear to be under selective constraints: relatively few substitutions leading to amino acid replacements are accepted, silent substitutions leading to some codons (especially purine-terminated ones) are disfavored, and different compositional biases are maintained in different parts of the sequences. Other sequence differences can be interpreted as indicative of neutral drift, including most differences in non-coding regions and most T/C transitions in third-base positions. In the non-coding regions, which are thought to be only loosely constrained by selection, transitions are observed more frequently than might be expected: they account for 52% of all substitutions, and they appear to be favored two to threefold over transversions when allowance is made for the skewed base composition of these regions.     

Synthesis and immunological activities of novel agonists of toll-like receptor 9

Novel agonists of TLR9 with two 5′-ends and synthetic immune stimulatory motifs, referred to as immune modulatory oligonucleotides (IMOs) are potent agonists of TLR9. In the present study, we have designed and synthesized 15 novel IMOs by incorporating specific chemical modifications and studied their immune response profiles both in vitro and in vivo. Analysis of the immunostimulatory profiles of these IMOs in human and NHP cell-based assays suggest that changes in the number of synthetic immunostimulatory motifs gave only a subtle change in immune stimulation of pDCs as indicated by IFN-α production and pDC maturation while the addition of self-complementary sequences produced more dramatic changes in both pDC and B cell stimulation. All IMOs induced cytokine production in vivo immediately after administration in mice. Representative compounds were also compared for the ability to stimulate cytokine production in vivo (IFN-α and IP-10) in rhesus macaques after intra-muscular administration.     

Role of toll-like receptors in tissue repair and tumorigenesis

Toll-like receptors (TLRs) play a critical role in host defense from microbial infection. TLRs recognize conserved molecular structures produced by microorganisms and induce activation of innate and adaptive immune responses. The inflammatory responses induced by TLRs play an important role TLRs not only in host defense from infection, but also in tissue repair and regeneration. This latter function of TLRs can also contribute to tumorigenesis. Here we review recent progress in understanding the role of TLRs in cancer development.     

Toll样受体对病原寄生虫的天然免疫识别

Toll样受体是机体天然免疫系统最重要的模式识别受体之一,通过识别病原寄生虫的病原相关分子模式,活化依赖和非依赖于髓样分化因子88的信号转导通路,诱导干扰素、炎症因子、趋化因子等的表达以及树突状细胞的成熟,抵御病原寄生虫的感染。因此,以下综述了Toll样受体对原病寄生虫,尤其对动物寄生性原虫与蠕虫感染的模式识别与天然免疫应答机制,以进一步理解病原寄生虫与宿主相互作用的复杂性,为寄生虫病的有效防治提供理论参考。     

Studies on toll-like receptor stimuli responsiveness in HIV-1 and HIV-2 infections

Background: HIV-1 and HIV-2 are two related viruses with distinct clinical outcomes, where HIV-1 is more pathogenic and transmissible than HIV-2. The pathogenesis of both infections is influenced by the dysregulation and deterioration of the adaptive immune system. However, their effects on the responsiveness of innate immunity are less well known. Here, we report on toll-like receptor (TLR) stimuli responsiveness in HIV-1 or HIV-2 infections. Methods: Whole blood from 235 individuals living in Guinea-Bissau who were uninfected, infected with HIV-1, infected with HIV-2, and/or infected with HTLV-I, was stimulated with TLR7/8 and TLR9 agonists, R-848 and unmethylated CpG DNA. After TLR7/8 and TLR9 stimuli, the expression levels of IL-12 and IFN-α were related to gender, age, infection status, CD4⁺ T cell counts, and plasma viral load. Results: Defective TLR9 responsiveness was observed in the advanced disease stage, along with CD4⁺ T cell loss in both HIV-1 and HIV-2 infections. Moreover, TLR7/8 responsiveness was reduced in HIV-1 infected individuals compared with uninfected controls. Conclusions: Innate immunity responsiveness can be monitored by whole blood stimulation. Both advanced HIV-1 and HIV-2 infections may cause innate immunity dysregulation.     

Role of toll-like receptors in lung cancer

Abstract

Lung cancer is a leading cause of death world-wide and the long-term survival rate for patients with lung cancer is one of the lowest for any cancer. Toll-like receptors (TLRs), evolutionarily conserved innate, are expressed in a wide variety of tissues and cell types, and they play key role in the innate immune system. TLRs have been found to be expressed by some kinds of tumor cells. However, what is the biological function of TLRs on tumor cells and whether human lung cancer cells can express TLRs remain to be fully understood. This review was performed to sum up the role of TLRs in lung cancer.     

Functions of toll-like receptors: lessons from KO mice

The innate immune response is a first-line defense system in which individual Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns (PAMPs) and exert subsequent immune responses against a variety of pathogens. TLRs are composed of an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic domain that is homologous to that of the IL-IR family. Upon stimulation, TLR recruits a cytoplasmic adaptor molecule MyD88, then IL-IR-associated kinase (IRAK), and finally induces activation of NF-kappaB and MAP kinases. However, the responses to TLR ligands differ, indicating the diversity of TLR signaling pathways. Besides MyD88, several novel adaptor molecules have recently been identified. Differential utilization of these adaptor molecules may provide the specificity in the TLR signaling.     

Toll样受体识别机制及其生物学意义

Toll样受体介导的信号转导通路在对抗外来病原体的天然免疫应答中起重要作用。Toll样受体是一个天然模板识别受体家族,能识别固有性模板(微生物和哺乳动物所共有的病原相联的分子模板PAMPs)。Toll样受体通过巨噬细胞和其他免疫细胞来识别,其中TLR4识别内毒素、TLR2识别肽聚糖、TLR9识别细菌DNA、TLR5识别鞭毛蛋白、TLR3识别双链RNA等。本探讨了多种Toll受体家族成员在动物体内识别机理及功能,概述了其应用研究进展。     

Exon-intron structure and evolution of the Lipocalin gene family

The Lipocalins are an ancient protein family whose expression is currently confirmed in bacteria, protoctists, plants, arthropods, and chordates. The evolution of this protein family has been assessed previously using amino acid sequence phylogenies. In this report we use an independent set of characters derived from the gene structure (exon-intron arrangement) to infer a new lipocalin phylogeny. We also present the novel gene structure of three insect lipocalins. The position and phase of introns are well preserved among lipocalin clades when mapped onto a protein sequence alignment, suggesting the homologous nature of these introns. Because of this homology, we use the intron position and phase of 23 lipocalin genes to reconstruct a phylogeny by maximum parsimony and distance methods. These phylogenies are very similar to the phylogenies derived from protein sequence. This result is confirmed by congruence analysis, and a consensus tree shows the commonalities between the two source trees. Interestingly, the intron arrangement phylogeny shows that metazoan lipocalins have more introns than other eukaryotic lipocalins, and that intron gains have occurred in the C-termini of chordate lipocalins. We also analyze the relationship of intron arrangement and protein tertiary structure, as well as the relationship of lipocalins with members of the proposed structural superfamily of calycins. Our congruence analysis validates the gene structure data as a source of phylogenetic information and helps to further refine our hypothesis on the evolutionary history of lipocalins.     

Parthenolide inhibits TRIF-dependent signaling pathway of toll-like receptors in RAW264.7 macrophages

Toll-like receptors (TLRs) play an important role in induction of innate immune responses for host defense against invading microbial pathogens. Microbial component engagement of TLRs can trigger the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent downstream signaling pathways. Parthenolide, an active ingredient of feverfew (Tanacetum parthenium), has been used for centuries to treat many chronic diseases. Parthenolide inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-κB kinase. However, it is not known whether parthenolide inhibits the TRIF-dependent pathway. To evaluate the therapeutic potential of parthenolide, its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly [I:C]) was examined. Parthenolide inhibited nuclear factor-κB and interferon regulatory factor 3 activation induced by LPS or poly[I:C], and the LPS-induced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10. These results suggest that parthenolide can modulate TRIF-dependent signaling pathways of TLRs, and may be the basis of effective therapeutics for chronic inflammatory diseases.     

Adaptive evolution in the rat olfactory receptor gene family

Summary Comparison of DNA sequences of the rat (Rattus norvegicus) olfactory receptor gene family revealed an unusual pattern of nucleotide substitution in the gene region encoding the second extracellular domain (E2) of the protein. In this domain, nonsynonymous nucleotide differences between members of this subfamily that caused a change in amino acid residue polarity were over four times more frequent than nonsynonymous differences that did not cause a polarity change. This nonrandom pattern of nucleotide substitution is evidence of past directional selection favoring diversification of the E2 domain among members of this subfamily. This in turn suggests that E2 may play some important role in the functions unique to each member of the olfactory receptor family, and that it may perhaps be an odorant binding domain.Offprint requests to: A.L. Hughes     

杨树MIR169基因家族分子进化分析

MicroRNA(miRNA)是真核生物中普遍存在的一类参与基因表达调控的小分子RNA。ptc-MIR169基因家族有33个成员, 是杨树中规模最大的miRNA基因家族。研究MIR169基因家族的进化对揭示杨树miRNA基因的进化机制具有重要的意义。文章对毛果杨MIR169基因家族的分子系统发育、基因倍增模式、表达分化和靶基因进行了分析。结果表明, 染色体大片段重复和串联重复在毛果杨MIR169基因家族扩张中均具有重要作用; MIR169基因家族在表达方式上已经出现了较大的分化; MIR169基因家族可能在杨树中已经形成了复杂的调控网络, 对杨树的生长发育和适应性等具有重要的调控作用。文章为杨树及杨柳科相关植物中miRNA基因家族的分子进化研究提供了参考。     

Regulation of gene expression of hepatic drug metabolizing enzymes and transporters by the Toll-like receptor 2 ligand, lipoteichoic acid

Expression of hepatic drug metabolizing enzymes (DMEs) is altered in infection and inflammation. However, the role of Gram+ve bacterial components and their receptor, Toll-like receptor (TLR) 2 in regulation of hepatic DMEs is unknown. Gene expression of DMEs is regulated by members of the nuclear receptor superfamily (PXR, CAR and RXRα). The TLR2 ligand, lipoteichoic acid (LTA) reduced RNA levels of CAR and its target genes, Cyp2b10, Cyp2a4 and Sultn in mouse liver (∼60-80% reduction). Hepatic genes regulated by PXR and CAR, Cyp3a11 and Mrp2 were moderately reduced by LTA, along with ∼50% reduction of PXR RNA and nuclear protein levels of RXRα. The effects of LTA were significantly attenuated by pre-treatment with the Kupffer cell inhibitor, gadolinium chloride, indicating that Kupffer cells contribute to LTA-mediated down-regulation of hepatic genes. These results indicate that treatment with Gram+ve bacterial components preferentially down-regulate CAR and its target genes in the liver.     

Regulation of Toll-like receptor signaling in innate immunity

Toll-like receptors sense invading pathogens by recognizing a wide variety of conserved pathogen-associated molecular patterns(PAMPs).The members of the TLR family selectively utilize adaptor proteins MyD88,TRIF,TIRAP and TRAM to activate overlapping but distinct signal transduction pathways which trigger production of different panels of mediators such as proinflammatory cytokines and type I interferon.These mediators not only control innate immunity but also direct subsequently developed adaptive immunity...