Members Of Toll-like Receptor Family Research Articles

Investigating the Role of Toll-Like Receptors in Mouse Models of Gastric Cancer.

Gastric cancer (GC) is the second most lethal cancer world-wide, and the poor overall 5-year survival rate of <25 % for GC is largely due to both the late detection of this aggressive disease and limited effectiveness of current treatment options. Collectively, these observations underscore the need to identify new molecular targets (i.e., genes) to serve as biomarkers for early detection and/or treatment strategies to improve patient outcomes. While GC represents a growing number of cancers whereby deregulation of the immune system is linked to tumor initiation and progression, the identity of innate immune regulators with oncogenic potential in the host gastric mucosal epithelium remains obscure. Over the last couple of decades experimental mouse models for many cancer types have been widely used with great success to identify genes whose expression and/or mutation status influences tumorigenesis. Considering the recent mounting evidence for the role of innate immunity in the pathogenesis of inflammation-associated cancers such as GC, much attention has focused on members of the Toll-like receptor (TLR) family, which are key components of the innate immune system primarily known to trigger inflammatory responses upon pathogen detection. Here, we describe techniques used on genetic mouse models for GC to examine the role of specific TLR family members in the pathogenesis of GC.

Expression levels of cytokines and chemokines increase in human peripheral blood mononuclear cells stimulated by activation of the Toll-like receptor 5 pathway.

Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) activates innate and adaptive immune responses. Among the 11 members of the human TLR family, TLR-5 is known to play an important role in the defense against bacterial invasion by binding to flagellin, a conserved component of bacteria. Previous studies have demonstrated that the activation of TLR-5 induces the expression of interleukin (IL)-10, IL-12 and interferon-β. However, the aim of the present study was to analyze the expression of a wider range of immune-related molecules upon stimulation with a TLR-5 agonist. Following isolation from healthy volunteers, peripheral blood mononuclear cells (PBMCs) were stimulated with flagellin, a TLR-5 agonist. At 4 h after stimulation, quantitative polymerase chain reaction (PCR) and an antibody chip array were conducted to determine the mRNA expression levels of immune molecules and the protein secretion of immune molecules in the supernatant, respectively. The PCR results revealed that activation of TLR-5 significantly influenced the expression of a number of important molecules. In addition, the antibody chip array demonstrated the induction (IL-8) and inhibition [monocyte chemoattractant protein (MCP)-1, MCP-3 and macrophage inflammatory protein-1α) of protein secretion following TLR-5 stimulation. Therefore, the present study demonstrated the importance of TLR-5 in regulating the biological function of PBMCs. In the future, research should focus on the roles of the candidate molecules in TLR-5-mediating functions.

IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

Toll-like receptors (TLR) and the receptor for interleukin-1 (IL-1R) signaling play an important role in bacteria-mediated bone loss diseases including periodontitis, rheumatoid arthritis, and osteomyelitis. Recent studies have shown that TLR ligands inhibit the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation from un-committed osteoclast precursors, whereas IL-1 potentiates RANKL-induced osteoclast formation. However, IL-1R and TLR belong to the same IL-1R/TLR superfamily, and activate similar intracellular signaling pathways. Here, we investigate the molecular mechanisms underlying the distinct effects of IL-1 and Porphyromonas gingivalis lipopolysaccharide (LPS-PG) on RANKL-induced osteoclast formation. Our results show that LPS-PG and IL-1 differentially regulate RANKL-induced activation of osteoclast genes encoding Car2, Ctsk, MMP9, and TRAP, as well as expression of NFATc1, a master transcription factor of osteoclastogenesis. Regulation of osteoclast genes and NFATc1 by LPS-PG and IL-1 is dependent on MyD88, an important signaling adaptor for both TLR and IL-1R family members. Furthermore, LPS-PG and IL-1 differentially regulate RANKL-costimulatory receptor OSCAR (osteoclast-associated receptor) expression and Ca(2+) oscillations induced by RANKL. Moreover, LPS-PG completely abrogates RANKL-induced gene expression of B lymphocyte-induced maturation protein-1 (Blimp1), a global transcriptional repressor of anti-osteoclastogenic genes encoding Bcl6, IRF8, and MafB. However, IL-1 enhances RANKL-induced blimp1 gene expression but suppresses the gene expression of bcl6, irf8, and mafb. Our study reveals the involvement of multiple signaling molecules in the differential regulation of RANKL-induced osteoclastogenesis by TLR2 and IL-1 signaling. Understanding the signaling cross-talk among TLR, IL-1R, and RANK is critical for identifying therapeutic strategies to control bacteria-mediated bone loss.

TMIC-03LOSS OF DAMAGE-ASSOCIATED MOLECULAR PATTERN SENSING IN CANCER STEM CELLS PROMOTES GLIOBLASTOMA MAINTENANCE

TMIC-03. LOSS OF DAMAGE-ASSOCIATED MOLECULAR PATTERN SENSING IN CANCER STEM CELLS PROMOTES GLIOBLASTOMA MAINTENANCE Alvaro Alvarado1,2, James Hale1, Erin Mulkearns-Hubert1, Daniel Silver1, and Justin Lathia1,2; Cleveland Clinic, Cleveland, OH, USA; Case Western Reserve University, Cleveland, OH, USA Glioblastoma (GBM) is composed of heterogeneous cellular populations, including self-renewing, tumorigenic cancer stem cells (CSCs). Discrete anatomical niches have been described where CSCs communicate with their surroundings to promote their self-renewal, tumor maintenance and increased resistance to conventional therapies. A hallmark of GBM is necrosis and the tumor microenvironment also contains many damage-associated molecular pattern molecules (DAMPs) that elicit an immune response and trigger cell death. These DAMPs are sensed by receptors such as those from the toll-like receptor (TLR) family, which have well-established roles in non-immune cells within the brain. The mechanisms by which CSCs but not other tumors cells can thrive despite DAMPs have yet to be elucidated. We analyzed the expression of TLR family members in patient-derived cells and found TLR4 was significantly decreased inCSCs comparedwith non-CSC. Bioinformatics analyses of patient datasets confirmed lower TLR4 expression is associated with poor prognosis. Stimulation of TLR4 induced a decrease in proliferation in non-CSCs, which was not observed in CSCs. Overexpression of TLR4 in CSCs decreased proliferation and self-renewal as well as expression of the stem cell markers SOX2, OCT4, NANOG, and OLIG2. We analyzed the promoter region of these critical genes and identified common transcription factors that were further validated by comparing their expression in CSCs vs. non-CSCs in a RNA-seq dataset. The expression of the top ten candidates was analyzed in the context of TLR4 overexpression. We identified Retinoblastoma binding protein 5 (RbBP5) as a potential key player in this signaling pathway. Mechanistic studies are in progress to determine how RbBP5 and TLR4 interact to regulate stem cell and self-renewal pathways. Our results link a damage-sensing receptor to a CSC-specific transcription factor that is upregulated in GBM and allows cells to tolerate hostile environmental cues. Neuro-Oncology 17:v221–v225, 2015. doi:10.1093/neuonc/nov236.3 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Expression patterns of Toll-like receptors in natural triploid Carassius auratus after infection with Aeromonas hydrophila

Toll-like receptors (TLRs) play the important roles in the innate immune system. In the present study, we have cloned fragments of 13 members of TLR family in natural triploid Qihe crucian carp (C. auratus) and investigated the expression profiles of these TLRs in spleen and head kidney at different time points after A. hydrophila infection. The results showed that the expressions of certain TLRs including TLR4, TLR5, and TLR22 were significantly up-regulated after infection, and the expression levels of TLR5 and TLR22 were the highest in spleen with 52.56-fold and 28.14-fold increase, respectively, whereas the other TLRs were down-regulated or no significant changes were observed compared with the control at most time points. These findings suggested that three TLRs (TLR4, TLR5, and TLR22) may play important roles in the immune responses of C. auratus to A. hydrophila infection. Additionally, the expression of most TLRs was significantly up-regulated at 6h post infection, which implied that the immune response of C. auratus reached the highest level at this time point. This work will facilitate our comprehensive understanding for the functions of TLRs in the process of bacterial infection in C. auratus and provide new insights for developing preventive and therapeutic measures against A. hydrophila infection.

Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes.

Toll-like receptors (TLRs) are known to recognize not only pathogen-associated molecular patterns but also danger-associated molecular patterns. Recent studies have characterized the expression levels and functions of TLRs in human epidermal cells. However, the characteristics of TLR family members in human dermal fibroblasts have not been thoroughly studied. Therefore, the present study systematically investigated the expression levels of TLRs and their functional responses to each ligand in skin fibroblasts. All 10 TLRs are expressed in skin fibroblasts. Stimulation of skin fibroblasts with each TLR ligand resulted in an increase of the interleukin-6 (IL-6), IL-8 and matrix metalloproteinase-1 proteins, indicating that ≥ 9 TLRs in skin fibroblasts are functionally active. Furthermore, stimulating skin fibroblasts with TLR1/2, 3 and 4 ligands induced the phosphorylation of inhibitor of nuclear factor κBα and the active phosphorylation of extracellular-signal regulated kinase 1/2. The expression level of each TLR was much higher in fibroblasts compared to keratinocytes. In particular, the fold-increase in IL-6 and IL-8 mRNA levels upon exposure to a TLR1/2 ligand was much higher in fibroblasts compared to keratinocytes, which appears to reflect the difference in expression levels of TLR1 and 2 between fibroblasts and keratinocytes. Taken together, these results show that all 10 TLRs are constitutively expressed and functional (except TLR10) in skin fibroblasts and suggest that TLRs in skin fibroblasts may play an important role in the detection of and response to different classes of pathogens and danger signals.

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Objectives The mechanisms that are involved in maintaining a human pregnancy to term, and the switches that lead to a normal labor and pregnancy outcome or indeed an adverse outcome such as miscarriage, preeclampsia, fetal growth restriction or preterm labor, are complex but the role of the placenta is crucial to them all. TLR family members are expressed differentially in a variety of cells and tissues. Toll-like receptors (TLR) are the principal signaling molecules through which mammals sense infection, so called innate immunity. Aims: The first aim of this study was to examine the spatial expression of TLRs in placentae obtained from women who delivered by caesarean section, and normal vaginal delivery, by defining precise sampling zones. The second aim was to determine the expression of TLRs in normal pregnancy with preeclampsia, both labor and non-labor. Methods Samples were obtained from 12 sites within each placenta: 4 equally spaced apart pieces were sampled from the inner, middle and outer placental zones. Non-labor, labor and preeclampsia were studied. TLRs gene expression was analyzed by RT-PCR using validated TaqMan® Gene Expression assays. Results There was a negotiable expression of TLR9 and 10 in the human placenta. There was a significant increase in TLR1 expression in the labor control compared to labor preeclampsia groups at the inner and middle sites ( p = 0.04, p = 0.002). TLR5 was significant increase in the non-labor group compared to labor group at the middle zones ( p = 0.004). No other differences were found. Conclusions TLRs may play a role in the physiology of labor and the pathology of pre-eclampsia. Disclosures A. Abdulsid: None. A. Fletcher: None. F. Lyall: None.

MyD88: a central player in innate immune signaling.

MyD88 is the canonical adaptor for inflammatory signaling pathways downstream of members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families. MyD88 links IL-1 receptor (IL-1R) or TLR family members to IL-1R-associated kinase (IRAK) family kinases via homotypic protein-protein interaction. Activation of IRAK family kinases leads to a variety of functional outputs, including the activation of nuclear factor-kappa B (NFκB), mitogen-activated protein kinases, and activator protein 1, making MyD88 a central node of inflammatory pathways. As more details of MyD88-dependent signaling have been elucidated, it has become clear that the functions of this critical signaling component can be influenced by multiple interaction partners in distinct subcellular compartments. In this review, we will focus on recent developments in the understanding of the assembly of MyD88 signaling complexes and the mechanisms leading to the diversification of MyD88-based signaling.

Molecular characterization and transcriptional analysis of non-mammalian type Toll like receptor (TLR21) from rock bream (Oplegnathus fasciatus)

Toll-like receptors (TLRs) are a large family of pattern recognition receptors, which are involved in triggering host immune responses against various pathogens by detecting their evolutionarily conserved pathogen associated molecular patterns (PAMPs). TLR21 is a non-mammalian type TLR, which recognizes unmethylated CpG DNA, and is considered as a functional homolog of mammalian TLR9. In this study, we attempted to identify and characterize a novel TLR21 counterpart from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at molecular level. The complete coding sequence of RbTLR21 was 2919bp in length, which encodes a polypeptide of 973 amino acids with a predicted molecular mass of 112kDa and a theoretical isoelectric point of 8.6. The structure of the deduced RbTLR21 protein is similar to that of the members of typical TLR family, and includes the ectodomain, which consists of 16 leucine rich repeats (LRRs), a transmembrane domain, and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. According to the pairwise sequence analysis data, RbTLR21 was homologous to that of the orange-spotted grouper (Epinephelus coioides) with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 is closely related to E. coioides TLR21. The RbTLR21 was ubiquitously expressed in all the tissues tested, but the highest expression was found in spleen. Additionally, upon stimulation with Streptococcus iniae, rock bream iridovirus (RBIV), and Edwardsiella tarda, RbTLR21 mRNA was significantly up-regulated in spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed an ortholog of the TLR21 family and may be important in mounting host immune responses against pathogenic infections.

Type III Secretion Needle Proteins Induce Cell Signaling and Cytokine Secretion via Toll-Like Receptors

Pathogens are recognized by hosts by use of various receptors, including the Toll-like receptor (TLR) and Nod-like receptor (NLR) families. Ligands for these varied receptors, including bacterial products, are identified by the immune system, resulting in development of innate immune responses. Only a couple of components from type III secretion (T3S) systems are known to be recognized by TLR or NLR family members. Known T3S components that are detected by pattern recognition receptors (PRRs) are (i) flagellin, detected by TLR5 and NLRC4 (Ipaf); and (ii) T3S rod proteins (PrgJ and homologs) and needle proteins (PrgI and homologs), detected by NAIP and the NLRC4 inflammasome. In this report, we characterize the induction of proinflammatory responses through TLRs by the Yersinia pestis T3S needle protein, YscF, the Salmonella enterica needle proteins PrgI and SsaG, and the Shigella needle protein, MxiH. More specifically, we determine that the proinflammatory responses occur through TLR2 and -4. These data support the hypothesis that T3S needles have an unrecognized role in bacterial pathogenesis by modulating immune responses.

Tying the knot between cytokine and toll‐like receptor signaling in gastrointestinal tract cancers

Inflammation-associated malignancies of the gastrointestinal tract (GI), including those of the stomach and colon, collectively rank as the highest cause of cancer-related deaths worldwide. It has been well documented that the deregulated activation of the archetypal pro-inflammatory and oncogenic transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription (STAT)3 is a common feature of GI cancers that invariably correlates with poor prognosis. Signal transducer and activator of transcription 3 and NF-κB are key downstream signal transducers of the interleukin (IL)-6 cytokine and toll-like receptor (TLR) families, respectively, and until recently, the potential involvement of these two families in the pathogenesis of cancer has been investigated in isolation. However, there is now emerging evidence of the complex interplay between the IL-6 cytokine and TLR families in GI tract cancers, with a surprising twist in the identification of a non-immune role for specific TLR family members. In this review, we discuss the molecular mechanisms associated with cross-talk between the IL-6 cytokine family/STAT3 signaling network and the TLR family/NF-κB signaling network, and we address the potential benefit of their therapeutic targeting in gastric and colorectal cancers.

Toll-like Receptor 11 (TLR11) Prevents Salmonella Penetration into the Murine Peyer Patches

Toll-like receptors (TLRs) are key molecular sensors used by the mammalian innate immune system to detect microorganisms. Although TLR functions in colonic immune homeostasis and tolerance to commensal bacteria have been intensively researched, the precise roles of different TLRs in response to pathogen infection in the gut remain elusive. Peyer patches are the major entrance of Salmonella infection and antigen transportation in intestine. Here, we report that, in contrast to TLR5 as a "carrier of Salmonella," TLR11 works as a "blocker of Salmonella" to prevent highly invasive Salmonella from penetrating into the murine Peyer patches and spreading systemically. TLR11 plays an important role in mediating TNF-α induction and systemic inflammation in response to Salmonella infection. Remarkably, in mice lacking TLR11, apparent hemorrhages at Peyer patches are induced by highly invasive Salmonella, a phenotype resembling human Salmonella infection. Therefore, our results indicate a potentially important role for TLR11 in preventing murine intestinal infection and modulating antigen transportation in the gut and imply an important role for various TLRs in cooperation with tight control of pathogens penetrating into Peyer patches. The TLR11 knock-out mouse can serve as a good animal model to study Salmonella infection.

Orange-spotted grouper (Epinephelus coioides) toll-like receptor 22: Molecular characterization, expression pattern and pertinent signaling pathways

The toll-like receptors (TLRs) are an important gene family in host innate immunologic surveillance. The TLR22 gene is an essential member of the TLRs that is only found in aquatic animals and has been detected in some bony fish. Here, a TLR22 homolog, EcTLR22, was characterized in the orange-spotted grouper (Epinephelus coioides) via homology cloning. The 3321 bp full-length cDNA sequence of EcTLR22 was obtained, which included an open reading frame of 2880 bp encoding a putative peptide of 960 amino acids containing three highly typical domains with the characteristics of TLR family members. The deduced amino acid sequence of EcTLR22 showed a relatively high similarity to flounder TLR22. Phylogenetic analysis showed that the orange-spotted grouper TLR22 sequence was clustered with those of Perciforme, such as flounder and croaker. Real-time quantitative PCR analysis revealed broad expression of EcTLR22, with relatively high expression detected in the head kidney, trunk kidney, spleen, peripheral blood leukocytes (PBLs) and heart of orange-spotted grouper. After injection with Vibrio alginolyticus, there was significant up-regulation of the expression of EcTLR22 in the spleen. In evaluating unstimulated/stimulated head kidney leukocytes and spleen leukocytes, a significant increase in EcTLR22 mRNA expression was detected, which implied a sensitive immune response. Furthermore, four important molecules for signal transduction, MyD88, TRIF, TNF-α and IRF3, were chosen to analyze the role of the EcTLR22 signaling pathway in anti-pathogen responses. Upon LPS or Poly I:C challenge, expression of the four genes was induced, with an increasing tendency detected in head kidney leukocytes, suggesting that the four genes might work with EcTLR22 in host defense against pathogenic microbes.

TLR2 activation of TRIF controls both early inflammatory and late tolerance responses to Borrelia burgdorferi (180.11)

Abstract TRIF is an adaptor molecule important in transducing signals from intracellularly signaling toll-like receptors (TLRs) 3 and 4, but not other TLR family members. Recently, TLR2 was found to signal from intracellular compartments. Using a synthetic ligand for TLR2/1 heterodimers as well as the bacterium Borrelia burgdorferi, which causes Lyme disease and is a strong activator of TLR2/1, we found that, contrary to current dogma, TLR2 signaling can utilize TRIF. Unlike TRIF signaling by other TLRs, TLR2-mediated TRIF signaling is dependent on the presence of another adaptor molecule, MyD88. However, unlike MyD88, TRIF deficiency does not result in diminished control of infection with B. burgdorferi. This appears to be due to the effects of MyD88 on phagocytosis via scavenger receptors such as MARCO which are not affected by the loss of TRIF. Although TRIF deficiency is associated with a decrease in pro-inflammatory cytokine induction in vitro, in an animal model of B. burgdorferi infection, loss of TRIF resulted in an increase in IL-6. In vitro studies mimicking longer exposures to B. burgdorferi show that TRIF mediates tolerance to the organism by suppressing pro-inflammatory cytokines disproportionately to anti-inflammatory cytokines in response to long term stimulation. Our studies suggest a dual role for TRIF in early and late TLR2 responses to infectious organisms.

TLR4 Overexpression After Orthotopic Liver Autotransplantation Contributes To Acute Lung Injury In Rats

Acute lung injury(ALI) is a common and severe complication of orthotopic liver transplantation(OLT), while the underlying mechanism of post‐OLT ALI is not very clear. Toll‐like receptor (TLR) 4 is an important TLR family member that plays a key role in the innate immune system. TLR4 is increased after OLT, accompanied with increased inflammatory response and ALI (Chin Med J, 2009,122:895–899). We hypothesized that TLR4‐mediated inflammation response may play a ctitical role in ALI during OLT. Healthy SD rats (n=8/group) were randomly divided into sham operated control group (C) and OLT groups with different durations (4, 8 and 16 hours) of reperfusion in the presence or absence of TLR4 siRNA interference performed 48 hours before OLT. Lung tissue TLR4 gene and protein expressions were significantly increased 8 hours after OLT and onwards, which was coincident with increased tissue levels of tumor necrosis factor (TNF) α, interleukin (IL)6 and IL‐1β, and evident lung pathological damage manifested as increased lung injury scores and increased lung water content and functional impairment manifested as reduced PaO2 (all P&lt;0.05 vs. OLT vs. C). TLR4 dominant negative siRNA prevented all the above changes after OLT. It is concluded that TLR4 overexpression, potentially by stimulting proinflammatory cytokine over production, plays a critical role in the developent of ALI after OLT.The study was supported by National Natural Science Foundation of China grant (No. 30801080 and 30972858).

TIR8/SIGIRR is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity

Interleukin-1R like receptors (ILRs) and Toll Like Receptors (TLRs) are key receptors of innate immunity, inflammation, and orientation of the adaptive response. They belong to a superfamily characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain, which is involved in the activation of a signaling cascade leading to activation of transcription factors associated to inflammation. The activation of inflammatory responses and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR dampens TLRs-mediated activation and inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33), and Th17 (IL-1) differentiation. Studies with Tir8/Sigirr-deficient mice showed that the ability to dampen signaling from ILRs and TLRs family members makes TIR8/SIGIRR a key regulator of inflammation. Here, we summarize our current understanding of the structure and function of TIR8/SIGIRR, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation.

Induction of toll-like receptor (TLR) 2, and MyD88-dependent TLR- signaling in response to ligand stimulation and bacterial infections in the Indian major carp, mrigal (Cirrhinus mrigala)

Toll-like receptor 2 (TLR2) is a member of TLR family. It recognizes a wide range of bacteria and their products, and is involved in inducing innate immune responses. In this article, we reported inductive expression of TLR2 and myeloid differentiation primary response gene 88 (MyD88)-dependent signaling in the Indian major carp, mrigal (Cirrhinus mrigala) which is highly commercially important fish species in the Indian subcontinent. Ontogeny analysis of TLR2, MyD88 and TRAF6 (TNF receptor associated factor 6) genes by quantitative real-time PCR (qRT-PCR) revealed constitutive expression of these genes in all embryonic developmental stages, indicating their involvement in embryonic innate immune defense system in fish. Tissue specific expression analysis of these genes by qRT-PCR showed their wide distribution in various organs and tissues. Highest expression of TLR2 was in gill, MyD88 in liver and TRAF6 was in kidney. Inductive expression of TLR2, MyD88 and TRAF6 genes were observed following peptidoglycan (PGN)-treatment, and Streptococcus uberis and Aeromonas hydrophila infections. Expression of interleukin (IL)-8 and TNF-α in various organs were significantly enhanced by PGN-treatment and bacterial infections, and were closely associated with TLR2 induction. These findings together highlighted the contribution of TLR2 in augmenting innate immunity in fish, and indicated it's important role in immune surveillance of various organs during pathogenic invasion. This study will enrich the information in understanding the innate immune mechanism in fish, and will be helpful in developing preventive measures against infectious diseases in fish.

Progress of Toll-like 9 receptors in Epstein-Barr virus infections

Toll-like receptor( TLR )is a newly discovered important innate immune receptor and signal transduction transmembrane receptor.By the TLR in the surface of immune cells,body can recognize conserved pathogen-associated molecular patterns,to stimulate the production of cytokine,increased costimulatory molecule expression of antigen-presenting cell,activating T cells,establishing a closely-linked bridge between the innate immunity and acquired immunity.TLR9 is a member of Toll-like receptor family,mainly identify viral or bacterial DNA containing unmethylated CpG dinucleotides.Studies have showed that TLR9 is in the immune system's recognition of EB virus,and it plays an important role in the infection and transformation of the EB virus.This paper reviews the studies of the interaction of TLR9 with EB virus. Key words: Toll-like receptors; Epstein-barr virus

Toll-like Receptor Signaling during Myocardial Ischemia

Acute myocardial infarction and myocardial ischemia are leading causes of short- and long-term morbidity and mortality in the perioperative period. In part, this relates to the fact that treatment options for a myocardial infarction in surgical patients are extremely limited. For example, anti-coagulation or treatment with highly effective inhibitors of platelet aggregation may not be an option due to the risk for bleeding from the operative site. Therefore, it is not surprising that the search for new pharmacologic approaches to treat myocardial ischemia or to render the myocardium more resistant to limited oxygen availability is an area of intense investigation for perioperative scientists.1-4 In fact, the introduction of intraoperative beta-blockers for cardio-protection from ischemia was one of the most significant alterations in anesthesia practice during the past fifteen years. In line with the search for novel therapeutic approaches to render the myocardium more resistant to ischemia, a very exciting research study by Wang et al. from the research laboratory of Dr. Wei Chao from the Anesthesia Center for Critical Care Research of the Massachusetts General Hospital in Boston provides new insight into signaling pathways involving toll-like receptor (TLR)-elicited cardio-protection from ischemia.1

A Novel Toll-like Receptor That Recognizes Vesicular Stomatitis Virus

Toll-like receptors (TLRs) are the key molecular sensors used by the mammalian innate immune system to detect various types of pathogens. Tlr13 is a novel and uncharacterized member of the mammalian TLR family. Here we report the cloning and characterization of tlr13. Tlr13 is predominantly expressed in the spleen, particularly in dendritic cells and macrophages. Tlr13 appears to activate a MyD88- and TAK1-dependent TLR signaling pathway, inducing the activation of NF-κB. This receptor can also activate type 1 interferon through IRF7. Furthermore, Tlr13 seems to be another intracellular TLR. Remarkably, cells expressing tlr13 fail to respond to known TLR ligands but instead respond specifically to vesicular stomatitis virus. Cells with the knockdown of tlr13 are highly susceptible to vesicular stomatitis virus infection. Thus, these results provide an important insight into the potential role of the novel Toll-like receptor tlr13 in the recognition of viral infection.