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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Streptococcus pneumoniae and Streptococcus agalactiae cause distinct infectious diseases in small children. Similarly, these bacteria elicit very different host-cell responses in vitro. Inactivated S. agalactiae by far exceeds S. pneumoniae in the activation of inflammatory cytokines and upstream signaling intermediates such as the MAP kinase JNK. The inflammatory response to both Streptococcus spp. is mediated by MyD88, an essential adapter protein of Toll-like receptors (TLRs), although the specific TLRs that are involved have not been fully resolved. Furthermore, during logarithmic growth, S. pneumoniae releases pneumolysin that interacts with TLR4 whereas S. agalactiae releases diacylated molecules that interact with TLR2/6. Interaction of these soluble bacterial products with their cognate TLRs is critical for limiting bacterial dissemination and and systemic inflammation in mice. This might be due, in part, to TLR-mediated apoptosis induced by these factors. In conclusion related streptococcal species induce specific events in TLR-mediated signal transduction. Comparative analysis of the host-cell response to these bacteria reveals molecules such as JNK as valuable targets for adjunctive sepsis therapy.
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PMID:Toll-like receptor-dependent discrimination of streptococci. 1705 94

Neisseria meningitidis causes acute severe diseases, including sepsis and meningitis, and more benign manifestations such as chronic meningococcemia or colonization of the upper respiratory tract. The inflammatory response, which contributes to the pathogenesis of meningococcal disease, is initiated by pattern recognition receptors, among which Toll-like receptors (TLR)s have been ascribed a particularly important role. We have previously demonstrated that N. meningitidis induce proinflammatory cytokine expression through TLR2 and TLR4. Here we characterize the molecular basis for differential activation of the inflammatory response by two N. meningitidis strains. This difference was due to differential ability to activate signal transduction through TLR4, as HEK293 cells expressing TLR4 produced significantly different levels of interleukin-8 in response to these strains. At the level of signal transduction, the two strains differed substantially in their ability to activate the pathway to nuclear factor kappaB in HEK293-TLR4/MD2 cells at late, but not early, time points. TLR4 activates two signal transduction pathways: one dependent on the adaptor molecule MyD88 and one independent of MyD88, and these pathways induce distinct patterns of gene expression in response to TLR4 ligands. By using macrophages from TLR2-/- mice, we observed that the two strains differed in their ability to activate the TLR4-induced MyD88-independent pathway, but not the MyD88-dependent pathway. This idea was further supported by experiments where either of the two pathways was inhibited and IL-8 secretion was measured. These data therefore provide molecular insight into activation of the inflammatory response by N. meningitidis, which is one of the key events in the pathogenesis of meningococcal disease.
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PMID:Two neisseria meningitidis strains with different ability to stimulate toll-like receptor 4 through the MyD88-independent pathway. 1708 21

TLRs are of crucial importance to the innate immune system by recognising molecules that are broadly shared by pathogens but distinguishable from host molecules. The innate immune system works to defend the body from microbial infection by initiating inflammation, the extreme form of which is sepsis. The discovery that endogenous ligands, as well as microbial components, are recognised by TLRs, raise the possibility of these receptors and their associated adapter molecules, as potential targets for the development of agonists and antagonists for the treatment of various pathological diseases, and their manipulation as potential adjuvants in vaccine development. By elucidating the mechanisms of TLR signalling pathways involving adapter molecules like MyD88, Mal, TRIF and TRAM combined with the identification of single nucleotide polymorphisms (SNPs) within these receptors and the unique genes that are expressed upon recognition, will assist in the development of therapeutics to alleviate the consequences of microbial-mediated inflammation, which include inflammatory disorders and septic shock.
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PMID:Toll-like receptor signalling and the clinical benefits that lie within. 1733 64

We recently showed that A(2A) adenosine receptor activation by endogenous adenosine contributes to interleukin-10 (IL-10) production in polymicrobial sepsis. Here we investigated the molecular mechanisms underpinning this interaction between adenosine receptor signaling and infection by exposing macrophages to Escherichia coli. We demonstrated using receptor knockout mice that A(2A) receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production by E coli-challenged macrophages, whereas A(2B) receptors have a minor role. The stimulatory effect of adenosine on E coli-induced IL-10 production did not require toll-like receptor 4 (TLR4) or MyD88, but was blocked by p38 inhibition. Using shRNA we demonstrated that TRAF6 impairs the potentiating effect of adenosine. Measuring IL-10 mRNA abundance and transfection with an IL-10 promoter-luciferase construct indicated that E coli and adenosine synergistically activate IL-10 transcription. Sequential deletion analysis and site-directed mutagenesis of the IL-10 promoter revealed that a region harboring C/EBP binding elements was responsible for the stimulatory effect of adenosine on E coli-induced IL-10 promoter activity. Adenosine augmented E coli-induced nuclear accumulation and DNA binding of C/EBPbeta. C/EBPbeta-deficient macrophages failed to produce IL-10 in response to adenosine and E coli. Our results suggest that the A(2A) receptor-C/EBPbeta axis is critical for IL-10 production after bacterial infection.
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PMID:A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli. 1752 87

Pathogens are sensed by pattern recognition receptors (PRRs), which are germ line-encoded receptors, including transmembrane Toll-like receptors (TLRs) and cytosolic nucleotide oligomerisation domain (NOD) proteins, containing leucine-rich repeats (NLRs). Activation of PRRs by specific pathogen-associated molecular patterns (PAMPs) results in genomic responses in host cells involving activation transcription factors and the induction of genes. There are now at least 10 TLRs in humans and 13 in mice, and 2 NLRs (NOD1 and NOD2). TLR signalling is via interactions with adaptor proteins including MyD88 and toll-receptor associated activator of interferon (TRIF). NOD signalling is via the inflammasome and involves activation of Rip-like interactive clarp kinase (RICK). Bacterial lipopolysaccharide (LPS) from Gram-negative bacteria is the best-studied PAMP and is activated by or 'sensed' by TLR4. Lipoteichoic acid (LTA) from Gram-positive bacteria is sensed by TLR2. TLR4 and TLR2 have different signalling cascades, although activation of either results in symptoms of sepsis and shock. This review describes the rapidly expanding field of pathogen-sensing receptors and uses LPS and LTA as examples of how these pathways parallel and diverge from each other. The role of pathogen-sensing pathways in disease is also discussed.
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PMID:Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease. 1753 71

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1(+)CD11b(+) population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1(+) cells effectively suppress antigen-specific CD8(+) T cell interferon (IFN) gamma production but only modestly suppress antigen-specific and nonspecific CD4(+) T cell proliferation. GR-1(+) cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell-dependent and depression of Th1 cell-dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain-containing adaptor-inducing IFN-beta, or the IFN-alpha/beta receptor, is required for complete GR-1(+)CD11b(+) expansion. GR-1(+)CD11b(+) cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.
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PMID:MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. 1754 19

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.
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PMID:E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. 1761 94

Repeated exposure to low doses of endotoxin results in progressive hyporesponsiveness to subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance. In spite of its clinical significance in sepsis and characterization of the TLR4 signaling pathway as the principal endotoxin detection mechanism, the molecular determinants that induce tolerance remain obscure. We investigated the role of the TRIF/IFN-beta pathway in TLR4-induced endotoxin tolerance. Lipid A-induced homotolerance was characterized by the down-regulation of MyD88-dependent proinflammatory cytokines TNF-alpha and CCL3, but up-regulation of TRIF-dependent cytokine IFN-beta. This correlated with a molecular phenotype of defective NF-kappaB activation but a functional TRIF-dependent STAT1 signaling. Tolerance-induced suppression of TNF-alpha and CCL3 expression was significantly relieved by TRIF and IFN regulatory factor 3 deficiency, suggesting the involvement of the TRIF pathway in tolerance. Alternatively, selective activation of TRIF by poly(I:C)-induced tolerance to lipid A. Furthermore, pretreatment with rIFN-beta also induced tolerance, whereas addition of IFN-beta-neutralizing Ab during the tolerization partially alleviated tolerance to lipid A but not TLR2-induced endotoxin homo- or heterotolerance. Furthermore, IFNAR1-/- murine embryonal fibroblast and bone-marrow derived macrophages failed to induce tolerance. Together, these observations constitute evidence for a role of the TRIF/IFN-beta pathway in the regulation of lipid A/TLR4-mediated endotoxin homotolerance.
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PMID:Role for MyD88-independent, TRIF pathway in lipid A/TLR4-induced endotoxin tolerance. 1778 47

Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-kappaB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-kappaB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IkappaB kinase-2/NF-kappaB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.
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PMID:Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. 1805 90

Sepsis remains a serious clinical problem because of high patient morbidity and mortality. Despite significant advances in critical care, there is still no efficient causal therapy applicable to patients indicating the need to further elucidate the molecular pathways leading to the immunopathology of sepsis. The importance of Toll-like receptors (TLR) for the induction of immune responses against sepsis was demonstrated in humans exhibiting polymorphisms in TLR genes and in animal models using genetically modified mouse strains. Because of the clinical heterogeneity in human sepsis and the complex pathomechanisms underlying sepsis, several different animal models might be used to cover the diverse features of sepsis. TLR receptors induce signaling through the adapter proteins MyD88 and TRIF. TLR signaling is tightly controlled at different steps of the signaling cascade by series of regulatory proteins. Using a model of severe polymicrobial septic peritonitis we could show that single TLRs are dispensable for the induction of innate immune responses under those conditions. However, genetic ablation of MyD88 or TRIF/type-I interferon signaling pathways prevented hyper-inflammation and attenuated the pathogenic consequences of sepsis indicating that dampening common signaling pathways may create a moderate signal strength which is associated with favorable immune responses. Therefore, broad knowledge about the regulation of TLR-induced signaling pathways may further elucidate the immune mechanisms during sepsis and targeting of TLR adapter molecules may provide a new therapeutic strategy against severe sepsis.
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PMID:Role of Toll-like receptor responses for sepsis pathogenesis. 1808 73


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