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)

Epidemiological studies suggest that intra-uterine exposure to inflammation may prime postnatal immune responses. In fetal sheep, intra-amniotic injection of lipopolysaccharide (LPS) induced chorioamnionitis, lung inflammation and maturation, matured lung monocytes to macrophages and initiated systemic tolerance of fetal monocytes to subsequent challenge with LPS. We hypothesized that LPS-mediated chorioamnionitis altered the response of lung and blood monocytes to Toll-like receptor (TLR) ligands such as PamCysK4 (TLR2), flagellin (TLR5), and human CpG-DNA (TLR9). Time-mated ewes were given intra-amniotic injections of LPS or saline. Blood and lung monocytes were assessed after 2 days, 7 days and 2 days and 7 days repetitive LPS injections before delivery at 124 days gestational age (term 150 days). Responsiveness of blood and lung monocytes to TLR-ligands in vitro was assessed by interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha) and hydrogen peroxide. Monocytes from preterm controls had minimal responses. Lipopolysaccharide-mediated chorioamnionitis increased IL-6, TNF- alpha and hydrogen peroxide to all TLR agonists in blood and lung monocytes. Repetitive exposure to antenatal LPS reduced IL-6, TNF- alpha and hydrogen peroxide to TLR-ligands suggesting tolerance. Tolerance to TLR-ligands reduced IL-1 receptor associated kinase-4 expression. Thus, repeated fetal exposure to LPS induced tolerance to other TLR-ligands. These modulations of fetal innate immunity have implications for host defense and injury responses in preterm infants.
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PMID:Intra-amniotic LPS modulation of TLR signaling in lung and blood monocytes of fetal sheep. 1931 20

Toll-like receptor 9 (TLR9) has been found to be the main receptor to respond to bacterial DNA in a wide variety of species. Recent work has shown that TLR9 is expressed in a diverse set of cells within the lung. However, much of this data has been centered on human and mouse cell culture lines or primary cultures and very little is known of TLR9 expression in intact lung, especially that of the horse. Here we show that TLR9 is expressed in the lungs of horses in a wide variety of cells. In particular, we note expression in pulmonary intravascular macrophages (PIMs), alveolar macrophages, bronchial epithelial cells, and type-II cells amongst others. Immunogold electron microscopy localized TLR9 in nuclei, cytoplasm, and plasma membrane of various lung cells. The data also show that E. coli lipopolysaccharide significantly increased expression of TLR9 mRNA in lungs and the number of cells in the lung septa that were positive for TLR9 protein. Protein expression was seen in airway epithelium, vascular endothelium, and inflammatory cells in blood vessels. Intravenous administration of gadolinium chloride, which depletes macrophages, before the lipopolysaccharide treatment significantly inhibited the LPS-induced increase in TLR9 mRNA in the lungs of the horses. We conclude that TLR9 is expressed in lung cells including PIMs and that the lipopolysaccharide treatment increases TLR9 mRNA expression. The increase in TLR9 mRNA is eliminated by depletion of PIMs, implicating these cells as a major source of TLR9 in the equine lung.
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PMID:Expression of toll-like receptor 9 in horse lungs. 1954 5

In this experiment Toll-like receptor expression pattern in monocytes and monocyte-derived macrophages by lipopolysaccharide (LPS) stimulation was examined. Jugular venous blood was collected from four Japanese calves, and the peripheral blood mononuclear cells (PBMCs) were isolated. The cells were directly used for collecting monocytes by magnetic cell sorting or cultured for 7 days to collect monocyte-derived macrophages in Repcell. Then we analyzed the mRNA expression pattern of TLRs and cytokines in monocytes and monocyte-derived macrophages after LPS stimulation for 24 h. LPS stimulation of both monocytes and monocyte-derived macrophages resulted in an increase in the levels of mRNA transcripts for TNF-alpha, IL-6 and IL-8. Moreover, TNF-alpha and IL-6 mRNA expressions were significantly augmented by LPS stimulation in monocyte-derived macrophages. TLRs mRNA expressions were unchanged after LPS stimulation of monocytes, while TLRs mRNA expressions in monocyte-derived macrophages were complicated. TLR1, 3, 5, 8 and 10 were significantly decreased after LPS stimulation and there were no differences in the mRNA expressions of TLR2, 4, 6 and 7 between the groups of control and LPS stimulation. Besides, no expression of TLR9 was found. As antigen presenting cells, monocytes and monocyte-derived macrophages respond differently to LPS, so they may have different functions in the innate immune system.
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PMID:Differential responses between monocytes and monocyte-derived macrophages for lipopolysaccharide stimulation of calves. 1956 6

Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been implicated to have a functional role in immune response, mainly at concentrations commensurate with pregnancy. However, the underlying mechanisms remain to be fully understood. Here we present the evidences that progesterone inhibited immune response to lipopolysaccharide (LPS) and CpG oligodeoxynucleotides (CpG ODNs) through modulating Toll-like receptor (TLR) signaling. Pretreatment with progesterone can significantly inhibit TLR4 and TLR9-triggered IL-6 and nitric oxide (NO) production in macrophages. Furthermore, we found that progesterone can significantly inhibit LPS-induced nitric oxide synthesis (iNOS), TLR4 expression and nuclear factor-kappaB (NF-kappaB) activation. Consistently, as a negative feedback inhibitor, the expression of suppressor of cytokine signaling (SOCS1) protein was up-regulated by progesterone in LPS-stimulated macrophages. These results support the concept that progesterone might inhibit innate immune response by suppressing NF-kappaB activation and enhancement of SOCS1 expression, providing a possible mechanistic explanation for the function of progesterone in regulating innate immune responses.
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PMID:Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. 1960 61

Stimulation of Toll-like receptors (TLRs) on macrophages and dendritic cells (DCs) by pathogen-derived products induces the production of cytokines, which play an important role in immune responses. Here, we investigated the role of the TPL-2 signaling pathway in TLR induction of interferon-beta (IFN-beta) and interleukin-10 (IL-10) in these cell types. It has previously been suggested that IFN-beta and IL-10 are coordinately regulated after TLR stimulation. However, in the absence of TPL-2 signaling, lipopolysaccharide (TLR4) and CpG (TLR9) stimulation resulted in increased production of IFN-beta while decreasing IL-10 production by both macrophages and myeloid DCs. In contrast, CpG induction of both IFN-alpha and IFN-beta by plasmacytoid DCs was decreased in the absence of TPL-2, although extracellular signal-regulated kinase (ERK) activation was blocked. Extracellular signal-related kinase-dependent negative regulation of IFN-beta in macrophages was IL-10-independent, required protein synthesis, and was recapitulated in TPL-2-deficient myeloid DCs by retroviral transduction of the ERK-dependent transcription factor c-fos.
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PMID:TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. 1966 62

Microglia express Toll-like receptors (TLRs) that recognize invading pathogens as well as endogenous proteins such as fibronectin under nonphysiological conditions. Here, we demonstrated that fibronectin stimulates murine microglia in culture in a dose-dependent manner: microglial cells secreted proinflammatory cytokines and chemokines and increased phagocytosis of Escherichia coli DH5alpha and E. coli K1 strains. Low levels of fibronectin exerted a synergistic effect on the release of proinflammatory compounds by microglia co-stimulated with agonists for TLR1/2 (Pam(3)CSK(4)) or TLR9 (CpG DNA), but not in combination with the TLR4 agonist lipopolysaccharide (LPS). Phagocytosis of bacterial strains was moderately enhanced when microglia was co-stimulated with high concentrations of fibronectin and one pathogen-derived TLR agonist. In conclusion, fibronectin increased proinflammatory and phagocytotic functions in microglia and partially synergized with microbial TLR agonists.
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PMID:Fibronectin stimulates Escherichia coli phagocytosis by microglial cells. 1978 Jan 98

When given passively or elicited actively, antibodies induced by a detoxified Escherichia coli Rc chemotype (J5) mutant lipopolysaccharide (J5dLPS)-group B meningococcal outer membrane protein (OMP) complex vaccine protected animals from lethal sepsis. The protection from sepsis is believed to be dependent on high levels of antibodies against the core glycolipid (CGL), a region of LPS that is rather conserved among Enterobacteriaceae. The addition of unmethylated deoxycytidyl-deoxyguanosine dinucleotide (CpG)-containing oligodeoxynucleotides (ODN) was used as an immuno-adjuvant to improve antibody responses. In preparation for a Phase I human trial, we elucidated potential contributions by which the sepsis vaccine (J5dLPS-OMP) and CpG ODN might enhance the antibody response and provide evidence that the generation of immune responses is Toll-like receptor (TLR) dependent. Toll-like receptor 2, TLR4, and TLR9 were each essential for generating robust cytokine and antibody responses. The signature cytokine of dendritic cells, interleukin-12, was one of the cytokines that demonstrated synergy with the optimal TLR ligand/ engagement combination. We conclude that the involvement of multiple TLRs upon immunization was critical for the generation of optimal antibody responses. These observations provide further evidence for the inclusion of innate immune-based adjuvants during the development of next-generation vaccines.
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PMID:Enhanced antibody responses to a detoxified lipopolysaccharide-group B meningococcal outer membrane protein vaccine are due to synergistic engagement of Toll-like receptors. 1982 32

The Toll-like receptors (TLRs) are a family of pathogen recognition receptors that alert the host to the presence of microbial challenge. Each TLR responds to a specific microbial associated ligand. For example, TLR4 is activated by lipopolysaccharide (LPS), whereas TLR9 responds to microbial DNA (CpGs). In this report signal transduction responses of bovine monocytes to stimulation with LPS and CpG are described through a bovine-specific peptide array. In addition to confirming activation of the defined TLR pathway in bovine cells, unique phosphorylation events not previously attributed to TLR signaling are described and validated. For example, array data predicts phosphorylation of Tyr40 of Etk in response to LPS, but not CpG, stimulation as well as the activation of oxidative burst in CpG, but not LPS. This investigation confirms interspecies conservation of the TLR pathway in bovine as well as providing insight into the complexity and mechanisms of TLR signaling.
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PMID:Kinome analysis of Toll-like receptor signaling in bovine monocytes. 1989 53

Toll-like receptors (TLRs) are crucial pattern recognition receptors in innate immunity that are expressed in microglia, the resident macrophages of the brain. TLR2, -4, and -9 are important in the responses against Streptococcus pneumoniae, the most common agent causing bacterial meningitis beyond the neonatal period. Murine microglial cultures were stimulated with agonists for TLR1/2 (Pam(3)CSK(4)), TLR4 (lipopolysaccharide), and TLR9 (CpG oligodeoxynucleotide) for 24 h and then exposed to either the encapsulated D39 (serotype 2) or the nonencapsulated R6 strain of S. pneumoniae. After stimulation, the levels of interleukin-6 and CCL5 (RANTES [regulated upon activation normal T-cell expressed and secreted]) were increased, confirming microglial activation. The TLR1/2, -4, and -9 agonist-stimulated microglia ingested significantly more bacteria than unstimulated cells (P < 0.05). The presence of cytochalasin D, an inhibitor of actin polymerizaton, blocked >90% of phagocytosis. Along with an increased phagocytic activity, the intracellular bacterial killing was also increased in TLR-stimulated cells compared to unstimulated cells. Together, our data suggest that microglial stimulation by these TLRs may increase the resistance of the brain against pneumococcal infections.
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PMID:Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. 1993 34

Mesenchymal stromal cells (MSC) are involved in tissue repair and in the regulation of immune responses. MSC express Toll-like receptors (TLR) known to link innate and adaptive immunity. We hypothesized that TLR signaling could influence human MSC (hMSC) function. Here, we show that hMSC express TLR1, TLR2, TLR3, TLR4, TLR5, and TLR6 but not TLR7, TLR8, TLR9, and TLR10. In inflammatory conditions mimicked by culturing hMSC in an inflammatory environment, TLR2, TLR3, and TLR4 are upregulated, whereas TLR6 is downregulated. Interleukin (IL)-1 beta, IL-6, IL-12p35 and transforming growth factor-beta mRNAs are constitutively expressed by hMSC. Inflammation leads to an increase in IL-1 beta, IL-6, IL-12p35, and transforming growth factor-beta transcription and is characterized by IL-23p19 and IL-27p28 transcription. In this setting, poly(I:C) further augments IL-6, IL-12p35, IL-23p19, and IL-27p28 transcription, whereas lipopolysaccharide (LPS) increases IL-23p19 and IL-27p28 transcription. By upregulating TLR3 and TLR4 transcription, inflammation increases the hMSC responsiveness to LPS and poly(I:C), leading to a proinflammatory shift in their cytokine profile. The hMSC osteogenic potential does not change after TLR triggering but stimulation with LPS and poly(I:C) results in a decrease in their immunosuppressive capabilities. In conclusion, TLR activation in hMSC may affect their function and could modify their in vivo fate, especially in an inflammatory context.
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PMID:Inflammation modifies the pattern and the function of Toll-like receptors expressed by human mesenchymal stromal cells. 2003 29


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