Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TLR4”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources
PubMed2003

Mycoplasma arthritidis superantigen (MAM)-induced macrophage nitric oxide release is MHC class II restricted, interferongamma dependent, and toll-like receptor 4 independent.

Mycoplasma arthritidis causes arthritis in rodents that resembles human rheumatoid arthritis. It produces a superantigen (MAM) that stimulates production of cytokines by making a bridge between lymphocyte T-cell receptor with the appropriate Vbeta chain, and H-2 1-Ealpha MHC class II molecules. Here we studied MAM-induced nitric oxide (NO) production in mouse peritoneal macrophages and found that it was: (1) time and concentration dependent, (2) possibly derived from inducible NOS synthase since it was reduced significantly by amino guanidine pretreatment, (3) restricted to H-2(K) (C3H/HePas and C3H/HeJ) and H-2(d) strains (BALB/c), (4) independent of TLR4 signaling since the coisogenic strains C3H/HePas and C3H/HeJ (TLR4 deficient) produced similar levels of NO following MAM stimulation, (5) potentiated by lipopolysaccharide, and (6) dependent on the presence of nonadherent peritoneal cells. Neutralization of interferon-gamma (IFNgamma in the peritoneal cell cultures with monoclonal antibodies abolished MAM-induced NO production. Addition of rIFNgamma to the adherent cells substituted the nonadherent cells for MAM-induced NO production. A macrophage cell line, J774A.1 (H-2(d)), also produced NO upon MAM stimulation but only when BALB/c spleen lymphocytes were added. Thus, in murine macrophages, MAM induces NO production that is dependent on signaling through MHC class II molecules and IFNgamma but independent of TLR4 expression.

Animals↗
PubMed2002

Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family.

The Toll/interleukin-1 (IL-1) receptor (TIR) family comprises two groups of transmembrane proteins, which share functional and structural properties. The members of the IL-1 receptor (IL-1R) subfamily are characterized by three extracellular immunoglobulin (Ig)-like domains. They form heterodimeric signaling receptor complexes consisting of receptor and accessory proteins. The members of the Toll-like receptor (TLR) subfamily recognize alarm signals that can be derived either from pathogens or the host itself. TLRs possess leucine-rich repeats in their extracellular part. TLRs can form dimeric receptor complexes consisting of two different TLRs or homodimers in the case of TLR4. The TLR4 receptor complex requires supportive molecules for optimal response to its ligand lipopolysaccharide (LPS). A hallmark of the TIR family is the cytoplasmic TIR domain that is indispensable for signal transduction. The TIR domain serves as a scaffold for a series of protein-protein interactions which result in the activation of a unique signaling module consisting of MyD88, interleukin-1 receptor associated kinase (IRAK) family members and Tollip, which is used exclusively by TIR family members. Subsequently, several central signaling pathways are activated in parallel, the activation of NFkappaB being the most prominent event of the inflammatory response. Recent developments indicate that in addition to the common signaling module MyD88/IRAK/Tollip, other molecules can modulate signaling by TLRs, especially of TLR4, resulting in differential biological answers to distinct pathogenic structures. Subtle differences in TLR signaling pathways are now becoming apparent, which reveal how the innate immune system decides at a very early stage the direction in which the adaptive immune response will develop. The creation of pathogen-specific mediator environments by dendritic cells defines whether a cellular or humoral response will be activated in response to the pathogen.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Differential regulation of Toll-like receptor mRNAs in experimental murine central nervous system infections.

Toll-like receptors (TLR) play a key role in the recognition of microbial components. We investigated the differential regulation of TLR mRNA expression in bacterial and viral mouse models of central nervous system infection. Streptococcus pneumoniae meningitis led to an enhanced expression of TLR2, TLR4 and TLR9 mRNA. In Escherichia coli meningitis, TLR2, TLR4 and TLR7 mRNA expression was increased and Herpes simplex encephalitis caused a rise of TLR4 mRNA. In organotypic hippocampal cultures treatment with S. pneumoniae R6 led to increased expression of TLR2 and TLR3 mRNA. Our data provide evidence that regulation of TLR mRNA is not fully specific for the molecular patterns of the infectious pathogen. The TLR mRNA regulation observed probably represents a combination of specific response to the causative pathogen and non-specific activation of the innate immune system.

Animals↗
PubMed2003

Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats.

OBJECTIVES: Apoptosis develops in several heart diseases, but the therapeutic options are limited. It was hypothesized that nicotine, which inhibits apoptosis in several cells, inhibits cardiac apoptosis induced by lipopolysaccharide (LPS). BACKGROUND: Over-the-counter nicotine produces sustained levels (10 to 25 ng/ml) that may be antiapoptotic. Low levels of LPS induce apoptosis by activating tissue renin-angiotensin to stimulate angiotensin II, type 1 (AT(1)) receptors in cardiac myocytes. METHODS: Adult Sprague Dawley rats were pretreated with nicotine (6 mg/kg/day) or saline for seven to ten days (miniosmotic pumps). The LPS (1 mg/kg) was injected intravenously. Toll-like receptor 4 (TLR4) and angiotensinogen messenger ribonucleic acid (mRNA) were measured in the heart after 0, 4, 8, 16, and 24 h. Cardiac apoptosis was measured by terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining after 24 h. In vitro effects of LPS (10 ng/ml, 24 h) were studied in cardiac myocytes isolated from rats pretreated with nicotine for 7 to 10 days, or after pre-exposing myocytes to nicotine (15 ng/ml) for 1, 4, 16, or 24 h. RESULTS: Neither nicotine nor LPS affected systolic blood pressure. The LPS increased cardiac apoptosis after 24 h in saline-treated, but not nicotine-treated rats, despite similar increases in cardiac TLR4 and angiotensinogen mRNA over 8 to 16 h. The LPS-induced apoptosis was blocked by pre-exposing myocytes to nicotine for 4 to 24 h (partial inhibition after 1 h). Nicotine did not inhibit apoptosis induced by angiotensin II (100 nM, 24 h). CONCLUSIONS: Therapeutic levels of nicotine inhibit LPS-induced cardiac apoptosis. This occurs after LPS increases TLR4 and angiotensinogen mRNA, but proximal to AT(1) receptor activation. Nicotine may be a novel inhibitor of cardiac apoptosis in conditions associated with circulating LPS (e.g., decompensated heart failure, acute and chronic infections).

Animals↗
PubMed2003

Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection.

Although various members of the pattern recognition Toll-like receptor (TLR) family have been implicated in host resistance to Mycobacterium tuberculosis infection, it remains unclear if the TLR4 receptor plays an important role. We demonstrate here that infection of TRL4-competent and TLR4-deficient mice on the C3H inbred mouse strain background had similar outcomes, measured in terms of the course of the disease, cell accumulation patterns in the lungs, and lung histopathology. These data argue against a significant role for TLR4 in immunity to tuberculosis in the mouse model.

Animals↗
PubMed2003

Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2.

Adaptive immunity generally refers to the ability of lymphocytes to recognize microbial, viral and fungal proteins via T cell receptors and antibodies. More ancestral and widespread innate immune mechanisms include those responsible for recognition of microbial glycolipids. Lipopolysaccharide (LPS) is the best studied, and arguably one of the most important of bacterial products because of its role in innate immune responses and endotoxin-mediated sepsis. Converging studies in two independent fields have recently led to the identification of LPS recognition molecules utilized by mammalian cells. Toll-like receptor 4 (TLR4) was identified as a mammalian homologue of the Toll receptor, which recognized fungi in the Drosophila's immune system. Spontaneous and targeted mutations identified TLR4 as an LPS recognition molecule. Separate studies of a Radioprotective 105 (RP105) and MD-1 heterodimer expressed by cells led to the identification of MD-2 as a molecule associated with TLR4. Very recent in vivo studies have now revealed an essential contribution of MD-2 to LPS recognition. These findings further our understanding of protective, as well as detrimental innate immune mechanisms and may lead to new therapies for endotoxin shock.

Animals↗
PubMed2003

Characterization of B cell membrane receptors of polysaccharide isolated from the root of Acanthopanax koreanum.

We investigated the immunomodulatory activity of polysaccharide isolated from the root of Acanthopanax koreanum (AK) at the cellular level. AK directly increased B cell proliferation and antibody production, but did not affect the expression of IL-2, IFN-gamma or IL-4 by T cells, or T cell proliferation in vitro. Since AK cannot penetrate cells due to its large molecular mass, B cell activation may be caused by the surface binding of AK to B cell-specific receptors. The role of TLR4 as an AK receptor was shown by the fact that AK activity in B cells from C3H/HeJ mice, which are known to have a defective Toll-like receptor (TLR)-4, was found to be reduced compared with that in control cells from C3H/HeN mice. AK activity was also reduced by antibodies blocking TLR2, TLR4, CD19 or CD79b, but not by an antibody blocking CD38, which suggests AK receptor profiling in B cells. Two main differences between AK and lipopolysaccharide (LPS) were observed. First, LPS activity was inhibited by antibodies to either TLR2 or TLR4, but not by antibodies to CD19, CD79b or CD38. Another was that LPS-induced B cell proliferation was inhibited by polymyxin B (PMB), a specific inhibitor of LPS, whereas AK activity was not affected. Taken together, our results demonstrate that AK directly activates B cells, but not T cells, and suggest that AK has a broader receptor profile than LPS in B cells.

Adjuvants, Immunologic↗
PubMed2006

Bovine beta-casein (1-28), a casein phosphopeptide, enhances proliferation and IL-6 expression of mouse CD19+ cells via Toll-like receptor 4.

This study was conducted to elucidate the target cells and receptors which participate in the mitogenic and interleukin (IL)-6-enhancing effect of bovine beta-casein (1-28), a casein phosphopeptide. When the spleen lymphocyte subset (CD4+, CD8+, and CD19+ cells) from C3H/HeN mice was cultured with the beta-casein (1-28), it exerted a dose-dependent mitogenic effect on CD19+ cells. The effect of beta-casein (1-28) was not apparent in the case of CD19+ cells from C3H/HeJ mouse. In addition, the effect was significantly inhibited by treating the C3H/HeN mouse-derived CD19+ cells with neutralizing antibody for toll-like receptor 4 (TLR4). Reverse transcription-polymerase chain reaction analysis showed that the beta-casein (1-28) exerted an IL-6-enhancing effect on the CD19+ cells. The effect was also abrogated in either C3H/HeJ mouse-derived CD19+ cell culture or the anti-TLR4 antibody-added culture. These results suggest that the beta-casein (1-28) stimulates both proliferation and IL-6 expression of CD19+ cells via TLR4.

Animals↗
PubMed2003

Contrasting responses of human gingival and periodontal ligament fibroblasts to bacterial cell-surface components through the CD14/Toll-like receptor system.

We compared human periodontal ligament fibroblasts with human gingival fibroblasts isolated from the same donor to examine interleukin-8 (IL-8) responses of the cells to Salmonella lipopolysaccharide, a water-soluble peptidoglycan from Staphylococcus epidermidis and the synthetic muramyldipeptide, with special reference to the possible involvement of the CD14/Toll-like receptor (TLR) system of the cells in the responses. Human gingival fibroblasts expressed CD14 on their surfaces and strongly expressed CD14 mRNA, while human periodontal ligament fibroblasts showed considerably lower levels of expression in both respects. Both cells expressed mRNA of TLR-related molecules, i.e. TLR2, TLR4, MD-2 and MyD88, although human periodontal ligament fibroblasts expressed TLR2 more strongly than human gingival fibroblasts. Human gingival fibroblasts exhibited a stronger IL-8 response than human periodontal ligament fibroblasts to lipopolysaccharide, while human periodontal ligament fibroblasts exhibited a response comparable to, or slightly stronger than, that of human gingival fibroblasts to S. epidermidis peptidoglycan and muramyldipeptide. The IL-8 responses of both cells to lipopolysaccharide and S. epidermidis peptidoglycan were completely inhibited by antihuman CD14 monoclonal antibody (MAb). The responses of both cells to lipopolysaccaride were significantly inhibited by antihuman TLR4 MAb, while those to S. epidermidis peptidoglycan were inhibited by antihuman TLR2 MAb. In contrast, muramyldipeptide activated both types of cells in a TLR2- and TLR4-independent manner, although the activities of muramyldipeptide on human gingival fibroblasts, but not human periodontal ligament fibroblasts, were significantly inhibited by anti-CD14 MAb.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways.

Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.

Adaptor Proteins, Vesicular Transport↗
PubMed2001

TIRAP: an adapter molecule in the Toll signaling pathway.

Mammalian Toll-like receptors (TLRs) recognize conserved products of microbial metabolism and activate NF-kappa B and other signaling pathways through the adapter protein MyD88. Although some cellular responses are completely abolished in MyD88-deficient mice, TLR4, but not TLR9, can activate NF-kappa B and mitogen-activated protein kinases and induce dendritic cell maturation in the absence of MyD88. These differences suggest that another adapter must exist that can mediate MyD88-independent signaling in response to TLR4 ligation. We have identified and characterized a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein (TIRAP) and have shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4. We have also shown that the double-stranded RNA-binding protein kinase PKR is a component of both the TIRAP- and MyD88-dependent signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Regulation of lung injury and repair by Toll-like receptors and hyaluronan.

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

Animals↗
PubMed2006

The role of Toll-like receptors in non-infectious lung injury.

The role of Toll-like receptors (TLRs) in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan (HA) accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-kappaB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.

Animals↗
PubMed2006

Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.

Immune responses are initiated when molecules of microbial origin are sensed by the Toll-like receptors (TLRs). We now report the identification of essential molecular components for the trafficking of the lipopolysaccharide (LPS) receptor complex. LPS was endocytosed by a receptor-mediated mechanism dependent on dynamin and clathrin and colocalized with TLR4 on early/sorting endosomes. TLR4 was ubiquitinated and associated with the ubiquitin-binding endosomal sorting protein hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs. Inhibition of endocytosis and endosomal sorting increased LPS signaling. Finally, the LPS receptor complex was sorted to late endosomes/lysosomes for degradation and loading of associated antigens onto HLA class II molecules for presentation to CD4+ T cells. Our results show that endosomal trafficking of the LPS receptor complex is essential for signal termination and LPS-associated antigen presentation, thus controlling both innate and adaptive immunity through TLR4.

Antigen Presentation↗
PubMed2001

IFNs activate toll-like receptor gene expression in viral infections.

Toll-like receptors (TLRs) mediate innate immune responses to microbes. TLR2, TLR5, TLR6, and TLR9 have been implicated in responses to bacterial components, and TLR4 is the receptor for Gram-negative bacteria. Recently, TLR4 was described to function in respiratory syncytial virus-induced NF-kappaB activation. Here we have analyzed TLR1-9 mRNA expression in human primary macrophages infected with influenza A and Sendai viruses. TLR1, TLR2, TLR4, TLR6, and TLR8 mRNAs were expressed at basal levels in macrophages. Viral infection enhanced TLR1, TLR2, TLR3, and TLR7 mRNA expression, and neutralizing anti-IFN-alpha/beta antibodies downregulated gene expression of these TLRs. Exogenously added IFN-alpha upregulated TLR1, TLR2, TLR3, and TLR7 mRNA expression in macrophages, as well as TLR3 mRNA expression in epithelial and endothelial cell lines. IFN-gamma enhanced the expression of TLR1 and TLR2 mRNA in macrophages, and TLR3 in epithelial and endothelial cells. The data suggests a novel role for IFNs in the activation of innate immunity.

Antibodies↗
PubMed2006

Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells.

Tubulointerstitial nephritis is a cardinal renal manifestation in leptospirosis and LipL32, the major lipoprotein component of leptospiral outer membrane proteins (OMPs), induces a robust inflammatory response in cultured renal proximal tubule cells through a nuclear factor-kappaB-related pathway. Here, we investigated whether Toll-like receptor (TLR), known to play a pivotal role in innate immunity, could mediate the inflammatory response induced by leptospiral OMPs in renal proximal tubule cells. TLR expression was analyzed by flow cytometry and indirect immunofluorescence in cultured mouse proximal tubule (pyruvate kinase simian virus 40-proximal straight (PKSV-PR)) cells. Reverse transcription-competitive polymerase chain reaction and enzyme-linked immunosorbent assay were undertaken to analyze the inducible effects of inducible nitric oxide synthase (iNOS) and monocyte chemoattractant protein-1 (MCP-1 also termed CCL2) by pathogenic and non-pathogenic leptospiral OMPs and recombinant lipoproteins in either PKSV-PR cells or TLR-transfected human embryonic kidney (HEK) 293 cells. Anti-TLR antibodies were used for blocking experiments. Leptospira santarosai serovar Shermani OMPs and LipL32 induced a significant increase in TLR2 but not TLR4 expression in PKSV-PR cells. The increase in iNOS and CCL2/MCP-1 mRNA expressions could be prevented by an anti-TLR2 antibody, but not by an anti-TLR4 antibody. Furthermore, leptospiral OMPs stimulated both CCL2/MCP-1 mRNA and secreted protein in transfected HEK 293 cells with a TLR2-expressing plasmid, but had no effect in cells with a TLR4-expressing plasmid. In conclusion, these findings indicate that the stimulation of iNOS and CCL2/MCP-1 caused by pathogenic leptospiral OMPs, in particular LipL32, in proximal tubule cells requires TLR2 for the early inflammatory response.

Animals↗
PubMed2003

Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome.

The systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality, and is thought to be due to an over-amplification of an inflammatory response. The Toll-like receptor 4 ( TLR4 ) Asp-299-->Gly polymorphism has been shown to reduce lipopolysaccharide responsiveness. We examined whether this TLR4 polymorphism is associated with severity of SIRS. A trend was found between the minor allele and mortality in SIRS (odds ratio of 4.3; P =0.076), suggesting a role for TLR4 signalling in the severity of SIRS.

APACHE↗
PubMed2003

Cell activation by monosaccharide lipid A analogues utilizing Toll-like receptor 4.

Lipid A is the bioactive centre of lipopolysaccharide (LPS), and its properties exhibit various endotoxic and biological effects toward host cells. We examined whether Toll-like receptors (TLRs) are mediated by the signals from various synthetic acylated derivatives of d-glucosamine monophosphate. All test synthetic monosaccharide lipid A analogues similar to acylated beta-(1-6)-d-glucosamine disaccharide bisphosphates, such as Escherichia coli-type lipid A (compound 506) and its precursor (compound 406), clearly induced nuclear factor (NF)-kappaB activation in Ba/F3 cells expressing murine TLR4 and its accessory protein MD-2 (Ba/mTLR4/mMD-2), but no induction was found in those expressing murine TLR2 (Ba/mTLR2). Compound 411, the non-reducing sugar moiety of compound 506, exhibited interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha)-producing activities in human peripheral blood mononuclear cells (PBMC), whereas compound 401, the reducing moiety of compounds 506 and 406, and Gifu lipid A-46 (GLA-46), the non-reducing moiety of compound 406, induced no production of IL-8 and TNF-alpha, which was similar to the findings for compound 406. Among the synthetic triacylated monosaccharide lipid A analogues, some compounds with three tetradecanoyl (C14) groups or that included a dodecanoyl (C12) group were more active toward murine and human cells than were other analogues with a decanoyl (C10) or hexadecanoyl (C16) group. Furthermore, IL-8 production in PBMC stimulated with the active monosaccharide lipid A analogues as well as compound 506 was clearly inhibited by the monoclonal antibody to human TLR4. These findings suggest that monosaccharide lipid A analogues similar to disaccharide lipid As are capable of activating both murine and human cells through TLR4.

Animals↗