Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Initial recognition of microbes, as they enter the body, is based on germ line-encoded pattern recognition receptors that selectively bind to essential components of pathogens. This allows the body to respond immediately to the microbial invasion before the development of active immunity. The signal-transducing receptors that trigger the acute inflammatory cascade have been elusive until very recently. On the basis of their genetic similarity to the Toll signaling pathway in Drosophila, mammalian Toll-like receptors (TLRs) have been identified. By now, nine transmembrane proteins in the TLR family have been described. Mammalian TLR4 is the signal-transducing receptor activated by the bacterial lipopolysaccharide. The activation of TLR4 leads to DNA binding of the transcription factor NF-kappaB, resulting in activation of the inflammatory cascade. Activation of other TLRs is likely to have similar consequences. TLR2 mediates the host response to Gram-positive bacteria and yeast. TLR1 and TLR6 may participate in the activation of macrophages by Gram-positive bacteria, whereas TLR9 appears to respond to a specific sequence of bacterial DNA. The TLRs that control the onset of an acute inflammatory response are critical antecedents for the development of adaptive acquired immunity. Genetic and developmental variation in the expression of microbial pattern recognition receptors may affect the individual's predisposition to infections in childhood and may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases.
 ...
PMID:Toll-like receptors as sensors of pathogens. 1151 16

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are critical for cellular responses to a variety of bacterial, viral, and fungal products. Mast cells are important to host survival in a number of models of bacterial infection and might act as sentinel cells in host defense. We therefore examined the expression of TLRs and associated molecules by murine bone marrow-derived mast cells (BMMCs). BMMCs and the murine mast cell line MC/9 expressed mRNA for TLR2, TLR4, and TLR6 but not TLR5 and for both adapter molecule MD-2 and signaling molecule MyD88 but lacked surface CD14. After activation with the TLR2- and TLR4-dependent stimuli Staphylococcus aureus-derived peptidoglycan and Escherichia coli-derived lipopolysaccharide (LPS), respectively, mast cells produced significant levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). To determine whether mast cells require TLR4 for cellular responses to LPS, mast cells were derived from the bone marrow cells of C3H/HeJ and C57Bl/10ScNCr mice containing a point mutation and a null mutation, respectively, in TLR4. Using these models, we demonstrated that the BMMC IL-6 and TNF-alpha responses to LPS were completely dependent on functional TLR4 with no significant LPS response observed in its absence. These findings have important implications for the mechanism of mast cell responses to pathogens and their products and suggest that different TLR4-expressing cells might have different thresholds for activation with LPS.
 ...
PMID:Toll-like receptor 4-mediated activation of murine mast cells. 1173 61

Innate immune response in Drosophila is mediated by signaling through Toll receptors. In mammals, Toll-like receptors (TLRs), comprising a large family, recognize a specific pattern of microbial components. So far, the roles of TLR2, TLR4, TLR5, TLR6, and TLR9 have been revealed. The recognition of microbial components by TLRs leads to activation of innate immunity, which provokes inflammatory responses and finally the development of adaptive immunity. The inflammatory response depends on a TLR-mediated MyD88-dependent cascade. However, there seems to exist additional cascades in TLR signaling. In the case of TLR4 signaling, an MyD88-independent pathway is now being characterized. In addition to the activation of innate immune responses, TLR-mediated signaling leads to suppression of the activity of innate immune cells, represented by "lipopolysaccharide (LPS) tolerance". Progress in elucidating the molecular mechanisms for LPS tolerance has been made through the analysis of TLR-mediated signaling pathways. Thus, the activity for innate immune responses is known to be finely regulated by TLRs.
 ...
PMID:Regulation of innate immune responses by Toll-like receptors. 1186 2

The innate immune system is in the vanguard of host defenses against infection. Recognition of invasive microbial pathogens is mediated by pattern recognition receptors on the surface of immune cells that recognize pathogen-associated molecular motifs. Considerable progress has been made in recent years in understanding how bacterial products initiate sepsis. In gram-negative sepsis, the LPS-binding protein (LBP), CD14 and the recently identified Toll-like receptor 4 (TLR4) are key molecules for the recognition of endotoxin (lipopolysaccharide, LPS) by cells of the myelomonocytic lineage. In gram-positive sepsis, components of the bacterial cell wall (peptidoglycan, PGN; lipoteichoic acids, LTA) have been shown to activate myeloid cells through an interaction with a receptor complex composed of CD14, TLR2 and perhaps also TLR6 (PGN) or CD14 and TLR4 (LTA). By contrast, gram-positive exotoxins act as superantigens and directly stimulate T lymphocytes by cross-linking the MHC class II of antigen presenting cells to specific chains of the T cell receptor. Immune cells activated by microbial pathogens release numerous effector molecules, which orchestrate the innate and adaptive host defenses. Furthermore, bacteria and microbial toxins directly activate the complement and coagulation systems, which play an important part in the host defensive response. Severe sepsis and septic shock can be viewed as clinical manifestations of a failing innate immune response that ultimately results in an overstimulation of the physiological host response. The pathogenesis of sepsis is far more complex that was initially anticipated. However, combined research efforts of basic scientists and clinical investigators continue to provide critical information for the identification of novel therapeutic targets. The exciting results obtained recently with treatment strategies designed to correct coagulation abnormalities occurring during sepsis are an example of how research may ultimately translate into improved patient care.
 ...
PMID:Pathogenesis of septic shock: implications for prevention and treatment. 1193 63

Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.
 ...
PMID:The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. 1244 42

Toll-like receptor (TLR) 2 is a member of the vertebrate protein family of TLRs that has been studied in substantial detail over the last years. The extracellular domain of the type I receptor molecule TLR2 contains 18 to 20 leucine rich repeat (LRR) and LRR like motives. The intracellular domain of TLR2 contains a Toll/IL-1 receptor/resistance protein typical TIR domain. After the first implication of TLR4 in immunity thereinafter followed by the discovery of the lipopolysaccharide signal transducer function of TLR4, TLR2 was the first of ten mammalian TLRs proven to be directly involved in recognition of pathogen associated molecular patterns (PAMPs). Among the TLR2 specific agonists are microbial products representing broad groups of species such as Gram-positive and Gram-negative bacteria, as well as mycobacteria, spirochetes, and mycoplasm. PAMP induced phagosomal localization of TLR2 and TLR2 dependent apoptosis have been shown. Complex formation with other molecules involved in pattern recognition such as CD14, MD2, TLR1, and TLR6 has been implicated for TLR2. Surprisingly even proteinaceous host material such as heat shock protein (HSP) 60 has been demonstrated to activate cells through TLR2. Thus, TLR2 may be a sensor and inductor of specific defense processes, including oxidative stress and cellular necrosis initially spurred by microbial compounds. Here we summarize the current knowledge on the structure and function of TLR2, which is far from being complete. Detailed understanding of the biology of TLR2 will probably contribute to the characterization of a number of infectious diseases and potentially help in the development of novel intervention strategies.
 ...
PMID:TLR2: cellular sensor for microbial and endogenous molecular patterns. 1246 48

NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-L-Ala-D-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of L-Ala for D-Ala or D-isoGln for L-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development.
 ...
PMID:Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. 1251 69

Toll-like receptors (TLRs) recognize and signal the presence of bacterial components such as lipopolysaccharide (LPS) and peptidoglycan (PG) as a part of innate immunity. Our previous studies revealed that mast cells function as effector cells in the protection of mice against lethal enterobacterial infections. In this study, we examined both the gene expression of molecules involved in TLR signaling and the effects of LPS and PG in bone marrow-derived cultured mast cells (BMCMCs). The mRNA expression of TLR2, TLR4 and TLR6 was detected in BMCMCs. CD14, MD-2 and MyD88, which are also involved in TLR pathway, were also expressed. Neither LPS nor PG affected degranulation in BMCMCs, but release of tumor necrosis factor increased slightly in response to LPS and PG. Both LPS and PG enhanced expression of pro-matrix metalloproteinase 9 (pro-MMP-9) in a dose-dependent manner, and DNA fragmentation was induced by LPS, but not by PG. These results suggest that mast cells are the targets of LPS and PG, and that the functions of these molecules produced exclusively by bacteria partly overlap, but are distinct.
 ...
PMID:Altered function of murine mast cells in response to lipopolysaccharide and peptidoglycan. 1285 56

Patients or experimental animals previously exposed to lipopolysaccharide (LPS) become tolerant to further LPS challenge. We investigated the potential of the macrophage-activating lipopeptide 2 (MALP-2) to induce in vivo cross tolerance to tumor necrosis factor alpha (TNF-alpha) and LPS. MALP-2-induced tolerance could be of practical interest, as MALP-2 proved much less pyrogenic in rabbits than LPS. Whereas LPS signals via Toll-like receptor 4 (TLR4), MALP-2 uses TLR2 and TLR6. LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2. No biologically active TNF-alpha could be detected in the serum of MALP-2-treated animals when challenged with LPS 24 or 72 h later, whereas suppression of LPS-dependent interleukin (IL)-6 lasted for only 24 h. Protection from lethal TNF-alpha shock was studied in galactosamine-treated mice. Dose dependently, MALP-2 prevented death from lethal TNF-alpha doses in TLR4(-/-) but not in TLR2(-/-) mice, with protection lasting from 5 to 24 h. To assay protection from LPS, mice were pretreated with MALP-2 doses of up to 10 micro g. Five and 24 h later, the animals were simultaneously sensitized and challenged by intravenous coinjection of galactosamine and a lethal dose of 50 ng of LPS. There was only limited protection (four of seven mice survived) when mice were challenged 5 h after MALP-2 pretreatment, and no protection when mice were challenged at later times. The high effectiveness of MALP-2 in suppressing TNF-alpha, the known ways of biological inactivation, and low pyrogenicity make MALP-2 a potential candidate for clinical use.
 ...
PMID:Toll-like receptor 2- and 6-mediated stimulation by macrophage-activating lipopeptide 2 induces lipopolysaccharide (LPS) cross tolerance in mice, which results in protection from tumor necrosis factor alpha but in only partial protection from lethal LPS doses. 1287 25

We successfully cloned and sequenced porcine toll-like receptor (TLR2) and TLR6 cDNA from porcine alveolar macrophages stimulated with 10 microg/ml lipopolysaccharide (LPS). The open reading frames (ORFs) of the porcine TLR2 and TLR6 cDNA were shown to be 2358 and 2391 bp in length and to encode 785 and 796 amino acids, respectively. The predicted amino acid sequence of porcine TLR2 was 72.3% homologous to human TLR2 and 61.0% homologous to murine TLR2. That of porcine TLR6 was 74.4% homologous to human TLR6 and 66.1% homologous to murine TLR6. Porcine TLR2 and TLR6 genes were both mapped to porcine chromosome 8 (TLR2: SSC8q21.1 --> 21.5; TLR6: SSC8p11.1 --> p21.1) by fluorescence in situ hybridization (FISH) and radiation hybrid mapping. Western blot analysis confirmed that TLR2 and TLR6 proteins were both expressed in porcine alveolar macrophages. Further, antiporcine TLR2 and TLR6 antibodies synergistically blocked tumor necrosis factor-alpha (TNF-alpha) production by porcine alveolar macrophages stimulated with Mycoplasma hyopneumoniae. These results indicated that both TLR2 and TLR6 are important in the recognition of M. hyopneumoniae in porcine alveolar macrophages and will be useful in understanding innate immunity against M. hyopneumoniae.
 ...
PMID:Porcine TLR2 and TLR6: identification and their involvement in Mycoplasma hyopneumoniae infection. 1458 98


1 2 3 4 5 Next >>