Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The life-threatening complications of sepsis in humans are elicited by infection with Gram-negative as well as Gram-positive bacteria. Recently, lipopolysaccharide (LPS), a major biologically active agent of Gram-negative bacteria, was shown to mediate cellular activation by a member of the human Toll-like receptor family, Toll-like receptor (TLR) 2. Here we investigate the mechanism of cellular activation by soluble peptidoglycan (sPGN) and lipoteichoic acid (LTA), main stimulatory components of Gram-positive bacteria. Like LPS, sPGN and LTA bind to the glycosylphosphatidylinositol-anchored membrane protein CD14 and induce activation of the transcription factor NF-kappaB in host cells like macrophages. We show that whole Gram-positive bacteria, sPGN and LTA induce the activation of NF-kappaB in HEK293 cells expressing TLR2 but not in cells expressing TLR1 or TLR4. The sPGN- and LTA-induced NF-kappaB activation was not inhibited by polymyxin B, an antibiotic that binds and neutralizes LPS. Coexpression together with membrane CD14 enhances sPGN signal transmission through TLR2. In contrast to LPS signaling, activation of TLR2 by sPGN and LTA does not require serum. These findings identify TLR2 as a signal transducer for sPGN and LTA in addition to LPS.
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PMID:Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. 1036 68

Group B streptococcus (GBS) imposes a major health threat to newborn infants. Little is known about the molecular basis of GBS-induced sepsis. Both heat-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-kappaB, the secretion of TNF-alpha, and the formation of NO in mouse macrophages. Macrophages from mice with a targeted disruption of MyD88 failed to secrete TNF-alpha in response to both heat-inactivated whole bacteria and GBS-F, suggesting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoundly from that by secreted GBS-F. Whole GBS activated macrophages independently of TLR2 and TLR6, whereas a response to the secreted GBS-F was not observed in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TLR4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular polysaccharide or beta-hemolysin had GBS-F activity comparable to that of wild-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as coreceptors for secreted microbial products derived from GBS and that cell wall components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.
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PMID:Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. 1173 28

During bacterial infections, the balance between resolution of infection and development of sepsis is dependent upon the macrophage response to bacterial products. We show that priming of murine bone marrow-derived macrophages (BMMs) with CSF-1 differentially regulates the response to two such stimuli, LPS and immunostimulatory (CpG) DNA. CSF-1 pretreatment enhanced IL-6, IL-12, and TNF-alpha production in response to LPS but suppressed the same response to CpG DNA. CSF-1 also regulated cytokine gene expression in response to CpG DNA and LPS; CpG DNA-induced IL-12 p40, IL-12 p35, and TNF-alpha mRNAs were all suppressed by CSF-1 pretreatment. CSF-1 pretreatment enhanced LPS-induced IL-12 p40 mRNA but not TNF-alpha and IL-12 p35 mRNAs, suggesting that part of the priming effect is posttranscriptional. CSF-1 pretreatment also suppressed CpG DNA-induced nuclear translocation of NF-kappaB and phosphorylation of the mitogen-activated protein kinases p38 and extracellular signal-related kinases-1/2 in BMMs, indicating that early events in CpG DNA signaling were regulated by CSF-1. Expression of Toll-like receptor (TLR)9, which is necessary for responses to CpG DNA, was markedly suppressed by CSF-1 in both BMMs and thioglycolate-elicited peritoneal macrophages. CSF-1 also down-regulated expression of TLR1, TLR2, and TLR6, but not the LPS receptor, TLR4, or TLR5. Hence, CSF-1 may regulate host responses to pathogens through modulation of TLR expression. Furthermore, these results suggest that CSF-1 and CSF-1R antagonists may enhance the efficacy of CpG DNA in vivo.
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PMID:Colony-stimulating factor-1 suppresses responses to CpG DNA and expression of toll-like receptor 9 but enhances responses to lipopolysaccharide in murine macrophages. 1175 85

Streptococcus pneumoniae is a leading cause of gram-positive sepsis, and lipoteichoic acid (LTA) may be important in causing gram-positive bacterial septic shock. Even though pneumococcal LTA is structurally distinct from the LTA of other gram-positive bacteria, the immunological properties of pneumococcal LTA have not been well characterized. We have investigated the ability of LTAs to stimulate human monocytes by using highly pure and structurally intact preparations of pneumococcal LTA and its two structural variants. The variants were pneumococcal LTA with only one acyl chain (LTA-1) and completely deacylated LTA (LTA-0). The target cells used in the study were peripheral blood mononuclear cells (PBMCs) and two model cell lines (CHO/CD14/TLR2 and CHO/CD14/TLR4) that express human CD25 protein in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation, respectively. Intact pneumococcal LTA and LTA-1 stimulated PBMC and CHO/CD14/TLR2 cells in a dose-dependent manner but did not stimulate CHO/CD14/TLR4 cells. Pneumococcal LTA was about 100-fold less potent than Staphylococcus aureus LTA in stimulating the CHO/CD14/TLR2 cells and PBMCs. LTA-0 (or pneumococcal teichoic acid) stimulated neither CHO/CD14/TLR2 nor CHO/CD14/TLR4 cells even at high concentrations. Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation. However, antibodies to CD14, TLR1, or TLR2 suppressed tumor necrosis factor alpha (TNF-alpha) production by PBMCs in response to LTA or LTA-1. These results suggest that pneumococcal LTA with one or both acyl chains stimulates PBMCs primarily via TLR2 with the help of CD14 and TLR1.
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PMID:Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. 1450 Apr 72

Microbes have on their surface molecular patterns that are common among a broad range of pathogens. These patterns are recognized by a wide variety of cellular receptors, the most important of which are a family of transmembrane proteins termed "Toll-like receptors" (TLR). TLRs are pattern-recognition receptors that have key roles in detecting pathogens and initiating inflammatory responses. The receptor of Gram negative bacterial LPS, TLR4, is the best characterized member of the TLR family. So far, ten mammalian toll-like receptors (TLR1-TLR10) have been identified. Recent studies revealed that the TLR signaling pathway is a critical mediator of sepsis. An understanding of TLRs and their signaling pathway will reveal a therapeutic target in sepsis and other immune mediated diseases.
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PMID:[Toll type receptors: molecular bases of the relationship between innate and adaptation responses of the immune system]. 1472 72

Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innate and adaptive immune responses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.
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PMID:Signaling danger: toll-like receptors and their potential roles in kidney disease. 1503 87

Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A-/- mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A-/- bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.
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PMID:A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. 1799 91

TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.
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PMID:Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. 1805 80

Toll-like receptors (TLRs) are crucial pattern-recognition receptors (PRRs) for activation of innate and adapted immunity. TLR2 heterodimerizes with TLR1 or TLR6 to recognize multiple pathogen-associated molecular patterns (PAMPs) of fungi, Gram-positive pathogens, and mycobacteria. Receptor activation culminates in monocyte, T-helper (Th)1, and Th2 cytokine release. Single nucleotide polymorphisms (SNPs) Arg753Gln and Arg677Trp affect TLR2 responsiveness and may contribute to the course of sepsis, which is associated with substantial morbidity and mortality during intensive care treatment. We genotyped 325 critically ill patients with septic shock, and performed a detailed clinical follow-up with 47 of these patients. Here, we investigated whether distinct sepsis episodes result in defined plasma cytokine patterns, and whether cytokine profiles may be linked to the TLR2 polymorphisms. Blood sampling was done daily and microbiological testing was performed on a routine basis. DNA was extracted from whole blood and TLR2 SNPs were typed by pyrosequencing. Cytokines were measured by multiplexed array technologies and the leukocyte phenotype was determined by flow cytometry. Among the 325 ICU patients, 17 individuals (5.2%) were heterozygous for Arg753Gln. The SNP Arg677Trp was not found in any patient. Episodes of Gram-negative, Gram-positive, and Candida sepsis were recorded. During Gram-positive sepsis, the cytokine pattern did not differ between Arg753Gln heterozygous patients and wild type patients. By contrast, during Candida sepsis, the Arg753Gln heterozygous patients showed biomarker patterns that differed from wild type patients with elevated TNF-alpha plasma concentrations, but reduced IFN-gamma and IL-8 levels. In conclusion, TLR2 SNP Arg753Gln results in altered cytokine release in response to Candida but not to Gram-positive sepsis.
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PMID:Pathogen specific cytokine release reveals an effect of TLR2 Arg753Gln during Candida sepsis in humans. 1824 33

Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria. It is a ligand for Toll-like receptor 4 (TLR4), which plays an essential role in innate immunity. Macrophages and dendritic cells exposed to LPS overproduce proinflammatory mediators, leading to septic shock. In this study, we screened for peptides that associate with TLR4 with a yeast two-hybrid screen using the human TLR4 extracellular domain as bait. A peptide (STM28) isolated from the screen inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation in human and mouse macrophage cells and interacted with TLR4 in yeast and mammalian cells. STM28 showed no inhibitory effects against NF-kappaB activation induced by TLR1/2, TLR3 and TLR9 ligands in a mouse macrophage cell line, RAW 264. In addition, STM28 suppressed LPS-induced tumor necrosis factor-alpha production by differentiated THP-1 cells. Moreover, LPS-induced lethality in d-galactosamine-sensitized mice was significantly repressed by STM28 in a dose-dependent manner. These results demonstrate that STM28 selectivity inhibits TLR4-induced macrophage activation, and suggest that STM28 may have utility as a novel therapeutic agent for Gram-negative bacterial sepsis.
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PMID:A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-kappaB and in vivo toxicity. 1870 Jan 40


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