Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-alpha) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to determine the mechanisms involved in its regulation. At a high concentration of LPS (10 ng/ml) and in the presence of autologous plasma, MNC from adults and newborns secreted similar amounts of TNF-alpha. However, in the absence of plasma, MNC from newborns secreted significantly less TNF-alpha compared to MNC from adults. Moreover, at a low concentration of LPS (0.1 ng/ml) and in the presence of plasma, TNF-alpha secretion was significantly lower for newborn MNC compared to adult MNC. Adults and newborns had similar numbers of CD14 and Toll-like receptor 4 (TLR-4)-positive cells as measured by flow cytometry. However, the intensity of the CD14 marker was greater for adult than for newborn cells. Incubation of cells with LPS led to an increase in CD14 and TLR-4 intensity for adult cells but not for newborn cells. The effect of LPS stimulation of adult or newborn cells was similar for ERK, p38, and IkappaBalpha phosphorylation, as well as IkappaBalpha degradation. Finally, we assessed levels of the TLR-4 adapter protein, the myeloid differentiation antigen 88 (MyD88). We found a direct relation between adult and newborn TNF-alpha secretion and MyD88, which was significantly decreased in newborn monocytes. Since TLR-4 signals intracellularly through the adapter protein, MyD88, we hypothesize that MyD88-dependent factors are responsible for delayed and decreased TNF-alpha secretion in newborn monocytes.
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PMID:Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. 1497 22

Genes encoding proteins with PYRIN/PAAD/DAPIN domains, a nucleotide binding fold (NACHT), and leucine rich repeats have recently been recognized as important mediators in autoimmune inflammatory disorders. Here we characterize the expression and function of a member of the PYRIN and NACHT domain (PAN) family, PAN1 (also known as NALP2 and PYPAF2). PAN1 protein expression is regulated by lipopolysaccharide (LPS) and interferons (IFNbeta and IFNgamma) in THP-1 macrophage cells. In gene transfection studies PAN1 manifests an inhibitory influence on NF-kappaB activation induced by various pro-inflammatory stimuli, including tumor necrosis factor TNFalpha and interleukin-1beta (IL-1beta). Gene transfer-mediated elevations in PAN1 protein also suppressed activation of IkappaB kinases induced by inflammatory cytokines. Conversely, reducing endogenous levels of PAN1 using small interfering RNA enhanced LPS-induced production of ICAM-1 (intercellular adhesion molecule 1), an NF-kappaB-dependent gene. We also show here that PAN1 binds via its PYRIN domain to ASC, an adapter protein involved in caspase-1 activation. This binding is disrupted by mutation of the alpha1 helix of ASC. In gene transfer experiments PAN1 enhances caspase-1 activation and IL-1beta secretion in collaboration with ASC. Conversely, reducing endogenous levels of PAN1 using small interfering RNA significantly reduced LPS-induced secretion of IL-1beta in monocytes. We propose that PAN1 functions as a modulator of the activation of NF-kappaB and pro-caspase-1 in macrophages.
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PMID:PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. 1545 91

Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-beta (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1beta and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc(-/-) mice. Upon stimulation with LPS, Asc(-/-) macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1beta and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-alpha and IL-6. MyD88(-/-) and Trif(-/-) macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc(-/-) mice lacked serum elevation of IL-1beta and IL-18. Moreover, the Asc(-/-) mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1beta/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases.
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PMID:ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules. 1550 17

The lung is continuously exposed to bacteria and their products, and has developed a complex defense mechanism, including neutrophil recruitment. In mice, keratinocyte cell-derived chemokine and macrophage inflammatory protein-2 are the major chemokines for neutrophil recruitment into the lung. We have previously described a role for C-X-C chemokine (CXCL5) in neutrophil trafficking during lipopolysaccharide (LPS)-induced lung inflammation in mice. The aims of the present study were to identify the cellular origin of CXCL5 and to determine the signaling cascades that regulate its expression in the lung during LPS-induced inflammation and in isolated LPS-stimulated CXCL5-expressing cells. Our immunohistochemical analysis indicates that alveolar epithelial type II (AEII) cells are the primary source of CXCL5 in the rodent lung. These in vivo observations were confirmed with primary AEII cells. In addition, our data indicate that the Toll-like receptor 4 (TLR4) signaling cascade involving TLR4, myeloid differentiation factor 88, and Toll-IL-1R domain-containing adapter protein is required to induce CXCL5 expression in the lung. Furthermore, p38 and c-Jun N-terminal kinases are involved in lung CXCL5 expression. Similarly, TLR4, and p38 and c-Jun N-terminal kinases, are associated with LPS-induced CXCL5 expression in AEII cells. These novel observations demonstrate that activation of AEII cells via TLR4-dependent signaling is important for the production of CXCL5 in the lung exposed to LPS.
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PMID:Induction of CXCL5 during inflammation in the rodent lung involves activation of alveolar epithelium. 1577 92

Alveolar macrophages (AMs) normally respond to lipopolysaccharide (LPS) by activating Toll-like receptor (TLR)-4 signaling, a mechanism critical to lung host defense against gram-negative bacteria such as Pseudomonas aeruginosa. Because granulocyte macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)) mice are hyporesponsive to LPS, we evaluated the role of GM-CSF in TLR-4 signaling in AMs. Pulmonary TNF-alpha levels and neutrophil recruitment 4 h after intratracheal administration of Pseudomonas LPS were reduced in GM(-/-) compared with wild-type (GM(+/+)) mice. Secretion of TNF-alpha by AMs exposed to LPS ex vivo was also reduced in GM(-/-) mice and restored in mice expressing GM-CSF specifically in the lungs (SPC-GM(+/+)/GM(-/-) mice). LPS-dependent NF-kappaB promoter activity, TNF-alpha secretion, and neutrophil chemokine release were reduced in AM cell lines derived from GM(-/-) mice (mAM) compared with GM(+/+) (MH-S). Retroviral expression of PU.1 in mAM cells, which normally lack PU.1, rescued all of these AM defects. To determine whether GM-CSF, via PU.1, regulated expression of TLR-4 pathway components, mRNA and protein levels for key components were evaluated in MH-S cells (GM(+/+), PU.1(Positive)), mAM cells (GM(-/-), PU.1(Negative)), and mAMPU.1+ cells (GM(-/-), PU.1(Positive)). Cluster of differentiation antigen-14, radioprotective 105, IL-1 receptor-associated kinase (IRAK)-M mRNA, and protein were dependent upon GM-CSF and restored by expression of PU.1. In contrast, expression of other TLR-4 pathway components (myeloid differentiation-2, TLR-4, IRAK-1, IRAK-2, Toll/IL-1 receptor domain containing adapter protein/MyD88 adaptor-like, myeloid differentiation primary-response protein 88, IRAK-4, TNF receptor-associated factor-6, NF-kappaB, inhibitor of NF-kappaB kinase) were not GM-CSF or PU.1-dependent. These results show that GM-CSF, via PU.1, enables AM responses to P. aeruginosa LPS by regulating expression of a specific subset of components of the TLR-4 signaling pathway.
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PMID:GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. 1691 76

Adhesion and degranulation promoting adapter protein (ADAP), a positive regulator of T cell receptor (TCR) signaling, is required for thymocyte development and T cell homeostasis. To investigate the role of ADAP in a T cell-driven autoimmune response, we generated ADAP-deficient, BDC2.5 TCR transgenic, diabetes-prone (C57BL/6) mice (BDC/B6). We observed a striking enhancement of diabetes incidence in ADAP-deficient mice, both in animals homozygous for I-Ag7, and in mice carrying one I-Ab allele (BDC/B6g7/b). Increased disease correlates with significantly reduced numbers of pathological CD4(+) T cells in the mice. Consistent with a state of functional lymphopenia in ADAP-deficient BDC/B6g7/b mice, T cells display increased homeostatic proliferation. Transfer of syngeneic lymphocytes or T cells both blocks ADAP-dependent diabetes and relieves exaggerated homeostatic T cell proliferation observed in ADAP-deficient mice. Marked attenuation in cellularity of the CD4+ single-positive thymocyte compartment in ADAP-deficient BDC/B6g7/b animals suggests a mechanism for induction of the lymphopenia. We conclude that inefficient positive selection in ADAP deficiency results in lymphopenia that leads to enhanced autoimmune diabetes in the BDC/B6g7/b model. Our findings support the notion that ineffective thymic T cell output can be a powerful causative factor in lymphopenia-driven autoimmune diabetes.
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PMID:Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice. 1838 41

Chronic inflammation and acute exacerbations are pathophysiological features of chronic obstructive pulmonary disease (COPD). An impaired immune response to bacterial pathogens can contribute to both of them. Nucleotide oligomerization domain 2 (NOD2) is an intracellular receptor of innate immunity for muramyldipeptide (MDP). Mutations of the NOD2 gene followed by decreased recognition of MDP are associated with chronic intestinal inflammation and pulmonary complications of patients with allogenic stem cell transplant and sepsis. Our study provides evidence that NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. We also demonstrate that lipopolysaccharide (LPS) can further increase NOD2 transcription in a TNF-alpha and IFN-gamma-induced activation state. In addition, we show that, while MDP fails to enhance CXCL-8 release from otherwise unstimulated BEAS-2B cells, a 12 h prestimulation period with TNF-alpha and IFN-gamma primes the cells for an additional increase of CXCL-8 secretion via induction of NOD2 and RIP2. LPS itself significantly augments CXCL-8 production and co-administration of MDP further increases cytokine secretion. Finally, overexpression of an SNP13 mutant decreased MDP-induced chemokine production in BEAS-2B cells compared with NOD2 wild type overexpression. Taken together, our work indicates that MDP and NOD2 play an important role for CXCL-8 release of BEAS-2B cells following LPS-challenge via synergistic interactions between MDP and LPS.
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PMID:Muramyldipeptide modulates CXCL-8 release of BEAS-2B cells via NOD2. 1864 46

Human neutrophils express Toll-like receptor 4 (TLR4) at low levels, and the role of this receptor in neutrophil responses to microbial stimuli has been questioned. Genetic manipulation of these cells to enable the study of the role of proteins such as TLR4 in their function is challenging. Here, we show that primary human neutrophils rapidly express novel proteins such as enhanced green fluorescent protein (eGFP) after transduction with lentivirus. Stimulation of transduced neutrophils with lipopolysaccharide (LPS) resulted in increased cell survival, which was inhibited when neutrophils were transduced with a lentivirus encoding a dominant negative (dn) TLR4 protein. LPS-induced survival was also inhibited by lentiviruses encoding dnMyD88 or a truncated TRIF (Toll/interleukin-1R homologous domain-containing adapter protein inducing interferon-beta) molecule, whilst, in contrast, neutrophil survival was enhanced by overexpression of kinase-mutated interleukin-1 receptor-associated kinase 1 (kmIRAK-1), which activated nuclear factor (NF)-kappaB. These studies provide proof of the role of TLR4 in human neutrophil biology, have begun to elucidate TLR-dependent pathways regulating neutrophil survival, and demonstrate that neutrophils can be genetically manipulated to enhance or inhibit survival.
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PMID:Pathways regulating lipopolysaccharide-induced neutrophil survival revealed by lentiviral transduction of primary human neutrophils. 1917

The adapter protein MyD88 adapter-like (Mal), encoded by TIR-domain containing adapter protein (Tirap) (MIM 606252), is the most polymorphic of the five adapter proteins involved in Toll-like receptor signaling, harboring eight non-synonymous single nucleotide polymorphisms in its coding region. We screened reported mutations of Mal for activity in reporter assays to test the hypothesis that variants of Mal existed with altered signaling potential. A TIR domain variant, Mal D96N (rs8177400), was found to be inactive. In reconstituted cell lines, Mal D96N acted as a hypomorphic mutation, with impaired cytokine production and NF-kappaB activation upon lipopolysaccharide or PAM2CSK4 stimulation. Moreover, co-immunoprecipitation studies revealed that Mal D96N is unable to interact with MyD88, a prerequisite for downstream signaling to occur. Computer modeling data suggested that residue 96 resides in the MyD88 binding site, further supporting these findings. Genotyping of Mal D96N in three different cohorts suggested that it is a rare mutation. We, thus, describe a rare variant in Mal that exerts its effect via its inability to bind MyD88.
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PMID:A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. 1950 86

Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor involved in inflammatory diseases and septic shock. The TREM-1 ligand(s) (TREM-1L) have not yet been identified. In this study, we performed a detailed analysis of the expression of mouse TREM-1 and its ligand(s). Our results demonstrate that TREM-1 is expressed on bone-marrow-derived dendritic cells (BMDC). On bone-marrow-derived macrophages (BMM) its expression is induced in vitro after stimulation by granulocyte-macrophage colony-stimulating factor, interleukin-3 or by myeloid differentiation primary response gene 88 (MyD88)-dependent Toll-like receptor (TLR) ligands. Under steady-state conditions mouse TREM-1 is detectable on a Gr-1(-) F4/80(+) monocyte subpopulation bearing markers of resident monocytes, but not on Gr-1(+) F4/80(+) inflammatory monocytes. During lipopolysaccharide (LPS)-induced endotoxaemia TREM-1 was also up-regulated on inflammatory Gr-1(+) F4/80(+) cells in vivo. In tumour-bearing mice, TREM-1 was up-regulated on Gr-1(+) F4/80(+) monocytes, which phenotypically and functionally resembled mononuclear myeloid-derived suppressor cells. Using a soluble TREM-1 fusion protein, we demonstrate that after intravenous injection of LPS TREM-1L was induced on Gr-1(+) granulocytes and monocytes but not on other cell populations in peripheral blood. This up-regulation on granulocytes was directly mediated by TLR ligands and required the adapter protein MyD88. In contrast to human, mouse platelets expressed TREM-1L neither under steady-state conditions nor after LPS injection in vivo. Our study reveals differential regulation of TREM-1 expression on mouse monocyte subpopulations and improves our understanding of the biological role of TREM-1 during disease.
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PMID:Regulation of triggering receptor expressed on myeloid cells 1 expression on mouse inflammatory monocytes. 1974 Mar 75


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