Oral administration of a synthetic agonist of Toll like receptor 9 potently modulates peanut induced allergy in mice. (2007 Sep)
Oral administration of a synthetic agonist of Toll like receptor 9 potently modulates peanut induced allergy in mice . background : agonists of Toll like receptor 9 have been shown to induce potent T ( H ) 1 type immune responses and prevent and reverse ovalbumin induced T ( H ) 2 dominant allergic asthma in mice . objective : We examined oral administration of a synthetic agonist of Toll like receptor 9 ( immune modulatory oligonucleotide IMO ) to modulate peanut induced allergy in mice . methods : In the prevention model mice were sensitized 3 times by means of oral administration of peanut in the presence or absence of IMO . In a treatment protocol mice were sensitized orally with peanut on days 0 and 14 and treated 4 times with oral administration of IMO starting on day 21 . results : In the prevention study mice that received the combination of IMO / peanut showed decreased IgE and increased igg2a levels in the serum and intestinal tissue compared with mice sensitized with peanut only . In spleen cell recall experiments , production of IL 5 and IL 13 was inhibited and production of IFN gamma was increased in mice immunized with the peanut / IMO combination compared with those sensitized with peanut only . In the treatment model IMO treated mice showed decreased IgE , IL 5 , and IL 13 levels and increased igg2a and IFN gamma levels in the serum , intestines , and spleen …

A46R and A52R from vaccinia virus are antagonists of host IL 1 and toll like receptor signaling. (2000 Oct)
A46R and A52R from vaccinia virus are antagonists of host IL 1 and toll like receptor signaling . poxviruses employ many strategies to evade and neutralize the host immune response . In this study , we have identified two vaccinia virus ORFs , termed A46R and A52R , that share amino acid sequence similarity with the Toll / IL 1 receptor ( TIR ) domain , a motif that defines the IL 1 / Toll like receptor ( TLR ) superfamily of receptors , which have a key role in innate immunity and inflammation . When expressed in mammalian cells , the protein products of both ORFs were shown to interfere specifically with IL 1 signal transduction . A46R partially inhibited IL 1 mediated activation of the transcription factor nfkappab , and A52R potently blocked both IL 1 and TLR4 mediated nfkappab activation . myd88 is a TIR domain containing adapter molecule known to have a central role in both IL 1 and TLR4 signaling . A52R mimicked the dominant negative effect of a truncated version of myd88 on IL 1 , TLR4 , and IL 18 signaling but had no effect on myd88 independent signaling pathways . therefore , A46R and A52R are likely to represent a mechanism used by vaccinia virus of suppressing TIR domain dependent intracellular signaling .

Toll like receptor polymorphisms and susceptibility to human disease. (2008 Jan)
Toll like receptor polymorphisms and susceptibility to human disease . although several lines of evidence suggest that variation in human inflammation is genetically controlled , the genes which regulate these responses are largely unknown . TLRs ( Toll like receptors ) mediate recognition of microbes , regulate activation of the innate immune response and influence the formation of adaptive immunity . cellular and molecular studies over the past several years have identified a number of common TLR polymorphisms that modify the cellular immune response and production of cytokines in vitro . In addition , human genetic studies suggest that some of these polymorphisms are associated with susceptibility to a spectrum of diseases . In this review , we summarize studies of common TLR polymorphisms and how this work is beginning to illuminate the influence of human variation on inflammation and disease susceptibility .

Intestinal inflammation in mice deficient in Tir8 , an inhibitory member of the IL 1 receptor family. (2004 Mar)
intestinal inflammation in mice deficient in Tir8 , an inhibitory member of the IL 1 receptor family . TIR8 , also known as single Ig IL 1 related receptor , is a member of the IL 1 receptor / Toll like receptor ( TLR ) superfamily , which acts as an intracellular decoy for components of the signaling pathway . Here we report that Tir8 has a unique pattern of expression , which includes mucosal tissues and dendritic cells ( DC ) . Tir8 deficient DC showed increased cytokine production in response to TLR agonists ( lipopolysaccharide , CpG oligodeoxynucleotides ) . Tir8 deficient mice had normal susceptibility to systemic lipopolysaccharide toxicity and to i . p . or s . c . inflammation . however , Tir8 deficient mice were more susceptible to intestinal inflammation . Thus , TIR8 represents a negative pathway of regulation of the IL 1 receptor / TLR system , expressed in epithelial cells and DC , crucial for tuning inflammation in the gastrointestinal tract .

Toll like receptors in borrelia burgdorferi induced inflammation. (2006 Jul)
Toll like receptors in borrelia burgdorferi induced inflammation . Lyme arthritis , the most common manifestation of late Lyme disease , has been associated with the presence of borellia burgdorferi in the joint . however , it is still unclear whether the pathogen itself is able to elicit such a sustained inflammatory response , or whether an aberrant immunological reaction of the host is the main driving force . borrelia antigens , including lipoproteins , flagellin and DNA , are ligands of Toll like receptors , and can thus elicit a strong stimulation of host cells , such as neutrophils , mononuclear cells and resident tissue cells . understanding the molecular basis of the signalling events caused by borrelia lipoproteins will lead to a greater understanding of inflammation in Lyme arthritis and , hopefully , new treatment strategies for chronic antibiotic resistant disease .

Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. (2008 May)
early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice . background : In mucopolysaccharidosis type IIIB , a lysosomal storage disease causing early onset mental retardation in children , the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation . We addressed causative links between the biochemical , pathological and inflammatory disorders in a mouse model of this disease . methodology / principal findings : In cell culture , heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll like receptor 4 and the adaptor protein myd88 . cd11b positive microglial cells and three fold increased expression of mrnas coding for the chemokine mip1alpha were observed at 10 days in the brain cortex of mpsiiib mice , but not in mpsiiib mice deleted for the expression of Toll like receptor 4 or the adaptor protein myd88 , indicating early priming of microglial cells by heparan sulfate oligosaccharides in the mpsiiib mouse brain . whereas the onset of brain inflammation was delayed for several months in doubly mutant versus mpsiiib mice , the onset of disease markers expression was unchanged , indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides . In contrast to younger mice , inflammation in aged mpsiiib mice was not affected by TLR4 / myd88 deficiency . conclusions / significance : these results indicate priming of microglia by HS oligosaccharides through …

Synergistic induction of cxcl9 and cxcl11 by Toll like receptor ligands and interferon gamma in fibroblasts correlates with elevated levels … (2004 May)
synergistic induction of cxcl9 and cxcl11 by Toll like receptor ligands and interferon gamma in fibroblasts correlates with elevated levels of cxcr3 ligands in septic arthritis synovial fluids . The synovial cavity constitutes the ideal stage to study the interplay between microbial Toll like receptor ( TLR ) ligands and cytokines . infiltrated leukocytes and synovial fibroblasts produce cytokine and chemokine induced proteases for remodeling the extracellular matrix . The regulation of chemokine function for attraction and activation of leukocytes constitutes a key feature in host immunity and resolution of inflammation after infection . enhanced levels of the CXC chemokine ligand ( cxcl9 ) / monokine induced by interferon gamma ( IFN gamma ) and cxcl11 / IFN inducible T cell alpha chemoattractant , two chemoattractants for activated T cells and natural killer cells , and ligands for CXC chemokine receptor 3 ( cxcr3 ) were detected in the synovial fluid of septic arthritis compared with osteo and crystal arthritis patients . In vitro , IFN gamma and TLR3 ligation by double stranded RNA ( dsrna ) induced the expression of cxcl9 and cxcl11 in leukocytes and skin muscle fibroblasts , whereas ligation of TLR2 , TLR4 , TLR5 , and TLR9 by peptidoglycan ( PGN ) , lipopolysaccharide ( LPS ) , flagellin , and unmethylated CpG oligonucleotides , respectively , did not . PGN and LPS , but not unmethylated CpG oligonucleotides , even inhibited IFN gamma induced cxcl9 and cxcl11 expression in leukocytes . In sharp contrast …

IL 6 : a regulator of the transition from neutrophil to monocyte recruitment during inflammation. (2002 Dec)
IL 6 : a regulator of the transition from neutrophil to monocyte recruitment during inflammation . The origin of the Toll like family of receptors pre dates the evolutionary split between the plant and animal kingdoms . these receptors are remarkably conserved across the taxonomic kingdoms and have fundamental roles in triggering immune responses . How they trigger such responses , and how these mechanisms arose in evolution , is a topic of extensive debate . We postulate a surveillance model : these receptors keep watch for both endogenous and exogenous molecules that indicate tissue inquiry , infection and remodeling . furthermore , we suggest that the first Toll like family receptors that arose in evolution might have acted in both development and immunity by recognizing the degradation of endogenous macromolecules .

Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll like receptor 4 signaling. (2003 Feb)
interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll like receptor 4 signaling . inflammatory arthritis is associated with the release of a network of key cytokines . In T cell receptor transgenic K / BxN mice interleukin ( IL ) 1 plays a key role in joint swelling and destruction , as suggested by the ability of anti IL 1receptor ( IL 1R ) antibody treatment to delay the onset and slow the progression of this disease . This mechanism is dependent on the signaling pathway intermediary myeloid differentiation factor 88 ( myd88 ) , such that neither IL 1R nor myd88 deficient mice developed visually detectable synovitis after transfer of arthritogenic sera . The Toll like receptors ( TLRs ) share the same signaling pathway through myd88 as the IL 1R . The administration of a TLR 4 ligand , lipopolysaccharide , concomitant with arthritogenic serum in IL 1 receptor deficient mice resulted in acute paw swelling , but not in myd88 deficient mice . Also , serum transferred arthritis was not sustained in TLR 4 mutant mice compared with controls . these results suggest that innate immune functions via TLR 4 might perpetuate inflammatory mechanisms and bypass the need for IL 1 in chronic joint inflammation .

Immunohistochemical localization of Toll like receptors 2 and 4 in gingival tissue from patients with periodontitis. (2003 Feb)
immunohistochemical localization of Toll like receptors 2 and 4 in gingival tissue from patients with periodontitis . The present study investigated the expression of Toll like receptor ( TLR ) 2 , TLR4 , cluster of differentiation ( CD ) 14 and CD1a in human periodontitis gingiva using immunohistochemical methods . The specimens were classified according to the degree of inflammation into three groups ( mild , moderate and severe ) . We established three zones in which to evaluate the ratios of TLR2 , TLR4 , CD14 and CD1a positive cells to total cells in the connective tissues of each section . TLR2 and TLR4 were expressed in human periodontal tissues , and the ratio of TLR2 positive cells was highest overall in zone 1 ( connective tissue subjacent to pocket epithelium ) of the severe group and that of TLR4 positive cells was higher in the severe group than in the other groups . these results suggest that TLR2 and TLR4 participate in the innate immune response to stimulation by bacterial products in periodontal tissues . The ratio of CD14 positive cells was lowest overall in zone 1 of the severe group and that of CD1a was higher in the severe group than in the other groups . these results suggest that CD14 may be down regulated during the development of inflammation and / or dendritic cells might infiltrate chronically inflamed gingival tissue .

Immunopathogenesis of onchocerca volvulus keratitis ( river blindness ) : a novel role for endosymbiotic wolbachia bacteria. (2003 Feb)
immunopathogenesis of onchocerca volvulus keratitis ( river blindness ) : a novel role for endosymbiotic wolbachia bacteria . river blindness is thought to occur as a result of the host response to degenerating microfilariae in the eye . utilizing a murine model of corneal inflammation ( keratitis ) to investigate the immune and inflammatory responses associated with river blindness , we recently demonstrated an important role for endotoxin like products from endosymbiotic bacteria and for activation of Toll like receptor 4 ( TLR4 ) . these observations have led to a new understanding of the pathogenesis of this disease

Sepsis : avoiding its deadly toll. (2004 May)
sepsis : avoiding its deadly toll . systemic bacterial infection may culminate in a frequently fatal septic shock syndrome . The underlying pathology is the result of an uncontrolled inflammatory response , stimulated by the pathogen and its products . Toll like receptors ( TLRs ) are critically involved in sensing bacteria and , in the case of sepsis , stimulate a pathogenic response by the innate immune system . A new study reports a successful attempt to inhibit systemic inflammation in mice by disrupting the formation of complexes between Gram positive bacteria and their cognate receptor , TLR2 .

Probiotics reduce the CD34 hemopoietic precursor cell increased traffic in allergic subjects. (2004 Jun)
probiotics reduce the CD34 hemopoietic precursor cell increased traffic in allergic subjects . An increased traffic of circulating CD34 hemopoietic precursors cells ( HPC ) is an important feature of systemic allergic inflammation . bacteria and bacterial products are capable of stimulating the transcription of the maturational cytokines IL12 and IFNs through the activation of Toll Like receptor and the subsequent nuclear translocation of the NF kappab factor . In this study the probiotics differentiation / maturational effect potential on CD34 HPC has been investigated . fourteen consecutive subjects , 9M and 5F , aged 6 48 , with clinical symptoms of asthma and / or conjunctivitis , rhinitis , urticaria , atopic dermatitis , food allergy and irritable bowel syndrome were enrolled . allergen specific serum IgE were found in twelve patients . Flow cytometric measurement of peripheral blood cd34dim / bright HPC values were assessed before and after 30 days of therapy , consisting in the oral administration of one sachet a day of endolac ( UCB pharma , turin , italy ) . Each sachet contained a mixture of lactobacillus acidophilus , L . delbrueckii and streptococcus thermophilus for a total of 1 x 10 ( 9 ) live bacteria . circulating CD34 cell values significantly ( p 0 . 001 ) reduced after the treatment . endolac , thus , may improve the efficacy of the standard treatments of allergic diseases .

The crystal structure of the human toll like receptor 10 cytoplasmic domain reveals a putative signaling dimer. (2008 Apr)
The crystal structure of the human toll like receptor 10 cytoplasmic domain reveals a putative signaling dimer . The Toll / interleukin 1 receptor ( TIR ) domain is a highly conserved signaling domain found in the intracellular regions of Toll like receptors ( TLRs ) , in interleukin 1 receptors , and in several cytoplasmic adaptor proteins . TIR domains mediate receptor signal transduction through recruitment of adaptor proteins and play critical roles in the innate immune response and inflammation . This work presents the 2 . 2A crystal structure of the TIR domain of human tlr10 , revealing a symmetric dimer in the asymmetric unit . The dimer interaction surface contains residues from the BB loop , DD loop , and alphac helix , which have previously been identified as important structural motifs for signaling in homologous TLR receptors . The interaction surface is extensive , containing a central hydrophobic patch surrounded by polar residues . The BB loop forms a tight interaction , where a range of consecutive residues binds in a pocket formed by the reciprocal BB loop and alphac helix . This pocket appears to be well suited for binding peptide substrates , which is consistent with the notion that peptides and peptide mimetics of the BB loop are inhibitors for TLR signaling . The tlr10 structure is in good agreement with available biochemical data on TLR receptors and is likely to provide a good model for the physiological dimer .

CD40 mediated up regulation of Toll like receptor 4 MD2 complex on the surface of murine dendritic cells. (2003 Dec)
CD40 mediated up regulation of Toll like receptor 4 MD2 complex on the surface of murine dendritic cells . Toll like receptors ( TLRs ) recognize pathogen associated molecular patterns , which are non self macromolecular components of pathogens that allow the innate immune system to recognize infection . TLRs are expressed on macrophages and dendritic cells ( DC ) . TLR stimulation or CD40 agonists can induce inflammatory cytokine secretion from macrophages and DC , and promote DC maturation . The regulation of TLR expression by inflammation has begun to be explored . Our studies have focused on the regulation of TLR4 surface expression on DC . TLR4 , along with the adaptor molecule MD2 , is involved in the recognition of lipopolysaccharide ( LPS ) . CD40 stimulation via cross linked anti CD40 monoclonal antibody ( mAb ) up regulates TLR4 MD2 surface expression on a DC cell line ( DC2 . 4 ) and on ex vivo cultured splenic DC . LPS treatment down regulated surface TLR4 MD2 on DC2 . 4 cells , but if combined with anti CD40 mAb , increased TLR4 MD2 expression was observed . The increased TLR4 MD2 surface expression by any treatment did not correlate with TLR4 mRNA levels . The functional consequence of increased TLR4 MD2 expression following LPS and anti CD40 treatment was examined . although CD40 prestimulation did slightly enhance interleukin 12p70 secretion after LPS restimulation , simultaneous anti CD40 mAb and LPS treatment , which up regulates …

Borrelia burgdorferi induces inflammatory mediator production by murine microglia. (2002 Sep)
borrelia burgdorferi induces inflammatory mediator production by murine microglia . Lyme disease has been associated with damaging inflammation within the central nervous system . In the present study , we demonstrate that borrelia burgdorferi is a significant stimulus for the production of IL 6 , TNF alpha , and PGE ( 2 ) by microglia . This effect is associated with induction of NF kappab , and increased expression of Toll like receptor 2 and CD14 , receptors known to underlie spirochete activation of other immune cell types . these studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B . burgdorferi . Such production may play an important role during the development of Lyme neuroborreliosis .

Toll like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. (2006 Mar)
Toll like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators . Toll like receptors ( TLRs ) are innate immunity receptors that are expressed on a wide range of cell types , including CNS glial cells . In general , TLR engagement by specific sets of microbial ligands triggers production of pro inflammatory factors and enhances antigen presenting cell functions . The functional roles of TLR in the CNS , however , are still poorly understood . while adult human astrocytes in culture dominantly express TLR4 , they display a strikingly strong and selective induction of TLR3 when activated by pro inflammatory cytokines , TLR3 or TLR4 agonists , or oxidative stress . Gene profiling analysis of the astrocyte response to either TLR3 or TLR4 activation revealed that TLR3 , but not TLR4 , induces expression of a range of neuroprotective mediators and several other molecules that regulate cellular growth , differentiation , and migration . Also , TLR3 triggered enhanced production of anti inflammatory cytokines including interleukin 9 ( IL 9 ) , IL 10 , and IL 11 and downregulation of the p40 subunit of IL 12 and IL 23 . The collective TLR3 induced products were found in functional assays to inhibit astrocyte growth , promote human endothelial cell growth , and importantly , to enhance neuronal survival in organotypic human brain slice cultures . together , our data indicate that TLR3 is induced on human astrocytes upon inflammation and when activated , mediates …

Inflammation , cancer and chemoresistance : taking advantage of the toll like receptor signaling pathway. (2007 Jan)
inflammation , cancer and chemoresistance : taking advantage of the toll like receptor signaling pathway . The association between chronic inflammation and cancer has long been observed . furthermore , NF kappab activation and the subsequent production of cytokines , chemokines , growth factors , and antiapoptotic proteins has been found to be involved in cancer progression and chemoresistance . however , the signals inducing NF kappab in cancer cells are still not well understood . Here , we reviewed the association between chronic inflammation and cancer , the role of NF kappab and its inhibitors as potential anticancer drugs , and Toll like receptors as possible signal initiators for NF kappab activation and inflammation induced carcinogenesis and chemoresistance . furthermore , we propose that , the stimulation of Toll like receptors by microbial components and / or endogenous ligands may represent the initial signal promoting a proinflammatory environment that will enhance tumor growth and chemoresistance .

Contribution of Toll like receptors to the innate immune response to Gram negative and Gram positive bacteria. (2007 Feb)
contribution of Toll like receptors to the innate immune response to Gram negative and Gram positive bacteria . innate recognition of bacteria is a key step in the activation of inflammation and coagulation , and it is dependent on pathogen associated molecular pattern ( PAMP ) ligation to Toll like receptors ( TLRs ) and CD14 . The dominant receptors activated when cells encounter a whole bacterium , which express several pamps , are poorly defined . herein , we have stimulated various human cells with prototypic Gram negative and Gram positive bacteria . receptor dependent responses to whole bacteria were assessed using both TLR transfected cells and specific monoclonal antibodies against TLRs , MD 2 , and CD14 . enterobacteria activated leukocytes and endothelial cells in a TLR4 / MD 2 dependent manner , most likely via lipopolysaccharide ( LPS ) . TLR2 activation was observed with a high bacterial inoculum , and in epithelial cells expressing TLR2 but not TLR4 . pseudomonas aeruginosa stimulated cells by both TLR2 and TLR4 / MD 2 . Gram positive bacteria activated cells only at high concentrations , in a partially TLR2 dependent but TLR4 / MD 2 independent manner . either TLR or CD14 neutralization blocked activation to all bacterial strains tested with the exception of some Gram positive strains in whole blood in which partial inhibition was noted . This study identifies dominant TLRs involved in responses to whole bacteria . It also validates the concept that host cell activation …

The etiology of sepsis : turned inside out. (2006 Jan)
The etiology of sepsis : turned inside out . The sepsis syndrome is thought to occur when microbial products activate Toll like receptors stimulating widespread inflammation , in turn causing organ failure , shock and death . however , recent discoveries reveal that : ( i ) not only microbial substances but also endogenous molecules can trigger Toll like receptors ; ( ii ) Toll like receptor 4 , the endotoxin receptor , is constitutively suppressed ; and ( iii ) the first step in sepsis could be the release of Toll like receptor 4 from suppression . these discoveries suggest that endotoxin might not always initiate the sepsis syndrome and they explain why anti endotoxin therapies fail . The discoveries also suggest new therapeutic targets endogenous agonists and Toll like receptor regulators for treatment of sepsis .