UNIPROT:P43026 - FACTA Search

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)

Stimulation of monocytes/macrophages with lipopolysaccharide (LPS) results in activation of nuclear factor-kappaB (NF-kappaB), which plays crucial roles in regulating expression of many genes involved in the subsequent inflammatory responses. Here, we investigated roles of transforming growth factor-beta activated kinase 1 (TGF-TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), in the LPS-induced signaling cascade. A kinase-negative mutant of TAK1 inhibited the LPS-induced NF-kappaB activation both in a macrophage-like cell line, RAW 264.7, and in human embryonic kidney 293 cells expressing toll-like receptor 2 or 4. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated upon simulation of RAW 264.7 cells with LPS. These results indicate that TAK1 functions as a critical mediator in the LPS-induced signaling pathway.
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PMID:TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages. 1067 30

Glucocorticoids and interleukin 10 (IL-10) prevent macrophage activation. In murine lymphocytes, glucocorticoids induce expression of glucocorticoid-induced leucine zipper (GILZ), which prevents the nuclear factor kappaB (NF-kappaB)-mediated activation of transcription. We investigated whether GILZ could account for the deactivation of macrophages by glucocorticoids and IL-10. We found that GILZ was constitutively produced by macrophages in nonlymphoid tissues of humans and mice. Glucocorticoids and IL-10 stimulated the production of GILZ by macrophages both in vitro and in vivo. Transfection of the macrophagelike cell line THP-1 with the GILZ gene inhibited the expression of CD80 and CD86 and the production of the proinflammatory chemokines regulated on activation normal T-cell expressed and secreted (CCL5) and macrophage inflammatory protein 1alpha (CCL3). It also prevented toll-like receptor 2 production induced by lipopolysaccharide, interferongamma, or an anti-CD40 mAb, as well as NF-kappaB function. In THP-1 cells treated with glucocorticoids or IL-10, GILZ was associated with the p65 subunit of NF-kappaB. Activated macrophages in the granulomas of patients with Crohn disease or tuberculosis do not produce GILZ. In contrast, GILZ production persists in tumor-infiltrating macrophages in Burkitt lymphomas. Therefore, GILZ appears to play a key role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL-10. Glucocorticoid treatment stimulates GILZ production, reproducing an effect of IL-10, a natural anti-inflammatory agent. The development of delayed-type hypersensitivity reactions is associated with the down-regulation of GILZ gene expression within lesions. In contrast, the persistence of GILZ gene expression in macrophages infiltrating Burkitt lymphomas may contribute to the failure of the immune system to reject the tumor.
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PMID:Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. 1239 3

In this study we investigated whether induction of toll-like receptor 2 (TLR2) amplifies the effect of a cell wall component derived from gram-positive bacteria, namely peptidoglycan (PGN). Mice received a first systemic lipopolysaccharide (LPS) injection to pre-induce TLR2 in various regions of the brain, and 6 h later, a second administration of either LPS or PGN. The data show a robust transcriptional activation of TLR2, TNF-alpha and monocyte chemotactic protein-1 (MCP-1) in microglial cells of mice challenged twice with LPS, whereas PGN essentially abolished this response. TLR4 plays a critical role in this process, because C3H/HeJ mice no longer responded to LPS but exhibited a normal reaction to PGN. Conversely, a robust signal for genes encoding innate immune proteins was found in the brain of TLR2-deficient mice challenged with LPS. However, the second LPS bolus failed to trigger TNF-alpha and IL-12 in TLR2-deficient mice, while the same treatment caused a strong induction of these genes in the cerebral tissue of wild-type littermates. The present data provide evidence that cooperation exists between TLR4 and TLR2. While TLR4 is absolutely necessary to engage the innate immune response in the brain, TLR2 participates in the regulation of genes encoding TNF-alpha and IL-12 during severe endotoxemia. Such collaboration between TLR4 and TLR2 may be determinant for the transfer from the innate to the adaptive immunity within the CNS of infected animals.
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PMID:Cooperation between toll-like receptor 2 and 4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteria. 1267 79

The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.
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PMID:Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system. 1286 Sep 70

The influence of an exercise training program and age on inflammatory cytokine production and CD14+cell-surface expression of toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) was examined in 60 younger and older subjects. Subjects were assigned to: young physically active (YPA, n = 15; 25.2 +/- 5.0 years), young physically inactive (YPI, n = 14; 24.9 +/- 4.7 years), older physically active (OPA, n = 14; 71.2 +/- 4.4 years) or older physically inactive (OPI, n = 17; 71.0 +/- 4.3 years) groups. YPI and OPI completed 12 weeks (3 days/week) of endurance (20 min) and resistance exercise (eight exercises, two sets). YPA and OPA groups were instructed to continue their normal activity for 12 weeks. Blood was collected at rest, before and after the 12-week training and control period. A whole blood method was used to determine lipopolysaccharide-(LPS) and peptidoglycan-(PGN) stimulated IL-6, IL-1beta, and TNF-alpha production with supernatants analyzed using ELISA. CD14+ cell-surface expression of TLR2 and TLR4 were measured using flow cytometry. Training increased estimated VO(2max) by 10.4% and increased strength by an average of 38.1%. YPI and OPI had a post-training reduction in LPS-stimulated IL-6 production (P < .01), but LPS-stimulated IL-1beta and TNF-alpha and PGN-stimulated cytokines were not changed. CD14+ cell TLR4 was significantly reduced (P < .05) in YPI and OPI groups after training, but TLR2 was not significantly changed. An exercise training program reduced LPS-stimulated IL-6, concomitant with lower TLR4. These results provide further support for a training- or physical activity-induced lowering of TLR4 and inflammation.
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PMID:Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4. 1596 85

Distinct from other spirochetes, cells of Leptospira interrogans contain orthologues of all the Escherichia coli lpx genes required for lipid A biosynthesis, but they synthesize a modified form of lipopolysaccharide that supposedly activates toll-like receptor 2 (TLR2) instead of TLR4. The recent determination of the L. interrogans lipid A structure revealed an unprecedented O-methylation of its 1-phosphate group (Que-Gewirth, N. L. S., Ribeiro, A. A., Kalb, S. R., Cotter, R. J., Bulach, D. M., Adler, B., Saint Girons, I., Werts, C., and Raetz, C. R. H. (2004) J. Biol. Chem. 279, 25420-25429). The enzymatic activity responsible for selective 1-phosphate methylation has not been previously explored. A membrane enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the 1-phosphate moiety of E. coli Kdo2-[4'-(32)P]lipid A has now been discovered. The gene encoding this enzyme was identified based on the hypothesis that methylation of a phosphate group is chemically analogous to methylation of a carboxylate moiety at a membrane-water interface. Database searching revealed a candidate gene (renamed lmtA) in L. interrogans showing distant homology to the yeast isoprenylcysteine carboxyl methyltransferase, encoded by sterile-14, which methylates the a-type mating factor. Orthologues of lmtA were not present in E. coli, the lipid A of which normally lacks the 1-phosphomethyl group, or in other spirochetes, which do not synthesize lipid A. Expression of the lmtA gene behind the lac promoter on a low copy plasmid resulted in the appearance of SAM-dependent methyltransferase activity in E. coli inner membranes and methylation of about 30% of the endogenous E. coli lipid A. Inactivation of the ABC transporter MsbA did not inhibit methylation of newly synthesized lipid A. Methylated E. coli lipid A was analyzed by mass spectrometry and NMR spectroscopy to confirm the location of the phosphomethyl group at the 1-position. In human cells, engineered to express the individual TLR subtypes, 1-phosphomethyl-lipid A purified from lmtA-expressing E. coli potently activated TLR4 but not TLR2.
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PMID:A Leptospira interrogans enzyme with similarity to yeast Ste14p that methylates the 1-phosphate group of lipid A. 1599 24

Lipoteichoic acid (LTA) is a major immunostimulatory molecule in the cell wall of Gram-positive bacteria. Adhesion of LTA to a polystyrene surface drastically increased its immunostimulatory potency in human whole blood in comparison to soluble LTA, although only 1% of the LTA had bound, as determined using rhodamine-labelled LTA. The release of the proinflammatory cytokines IL-1beta, TNF and IL-6 and the chemokines IL-8 and G-CSF was increased 2- to 10-fold, but IL-10 release was unaltered. This presentation effect was not shared by lipopolysaccharide (LPS) or other toll-like receptor 2 agonists and was less pronounced in polypropylene vessels. LTA did not induce cytokine release in silicone-coated borosilicate vessels, but covalent coupling of LTA to polystyrene beads restored cytokine induction in these vessels, indicating that presentation of LTA on a surface is in fact essential for its immunostimulatory potency. This novel aspect of presentation as a factor in the recognition of LTA may reflect the physiological situation in the bacterial cell wall, where LTA is anchored in the bacterial membrane and projects through the peptidoglycan. In practical terms, contamination of medical devices with components of Gram-positive bacteria may pose an underestimated inflammatory risk.
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PMID:Presentation of lipoteichoic acid potentiates its inflammatory activity. 1851 54

The periodontal ligament (PDL) is a fibrous connective tissue that exists in the cementum and the alveolar bone. Periodontitis is a chronic inflammatory disease that is caused by a bacterial infection in the periodontal region. This infection increases the production of inflammatory cytokines and causes the destruction of periodontal tissue. High mobility group box 1 (HMGB1) is a nuclear nonhiston DNA-binding protein that is present in many eukaryotic cells. HMGB1 is released actively from macrophages and monocytes stimulated by lipopolysaccharide or tumor necrosis factor-alpha and passively from damaged cells and necrotic cells. Extracellular HMGB1 signals through a specialized receptor for advanced glycation end products (RAGE), toll-like receptor 2 (TLR2), and toll-like receptor 4 (TLR4). According to a recent report, HMGB1 is of concern in periodontitis. The purpose of this study was to examine the effect of HMGB1 in PDL cells. To investigate RAGE, TLR2 and TLR4 mRNA in PDL cells, reverse transcript-polymerase chain reaction experiments were performed. PDL cells were stimulated with HMGB1, with or without anti-RAGE, TLR2 and TLR4 antibodies. IL-6 and IL-11 production was measured using an enzyme-linked immunosorbent assay, and mRNA expression was quantified by real-time PCR. PDL cells expressed RAGE, TLR2 and TLR4 mRNA. Production and mRNA expression of IL-6 and IL-11 were augmented in PDL cells stimulated with HMGB1. In addition, they were also suppressed by anti-RAGE, TLR2 and TLR4 antibodies. In conclusion, PDL cells produce IL-6 and IL-11 in response to HMGB1 via RAGE, TLR2 and TLR4.
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PMID:[Effect of high mobility group box 1 (HMGB1) in cultured human periodontal ligament cells]. 1904 16

The aim of this study was to determine whether stimulation of toll-like receptor 2 (TLR2), TLR4, and TLR6 by their specific ligands induces the production of tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) from interleukin-1 receptor antagonist (IL-1Ra)-deficient mice. FLS were isolated from synovial tissues from IL-1Ra-deficient mice and stimulated with various ligands of TLRs. The concentrations of TNF-alpha, interleukin (IL)-1beta, and IL-10 in the culture supernatants of spleen cells were measured by ELISA, and mRNA levels were assessed by real-time PCR. The expression of TLR2, TLR4, TLR6, and TNF-alpha in the synovial tissue was quantified by immunohistochemistry. Cytokine production and TLR expression were measured in FLS stimulated in the presence of the TLR2 ligand PAM3, the TLR4 ligand lipopolysaccharide (LPS), and the TLR6 ligand zymosan, with and without blocking antibody to TNF-alpha and IL-1beta. Stimulation of TLR2, TLR4, and TLR6 by their specific ligands increased the production of TNF-alpha in FLS from IL-1Ra-deficient mice. The stimulatory effect of these TLR ligands showed a dose-dependent pattern. The combination of TLR2, TLR4, and TLR6 synergistically increased the production of TNF-alpha, IL-1beta, TLR2, TLR4, and TLR6. Addition of blocking antibodies to TNF-alpha and IL-1beta abrogated the stimulatory effect of the ligands of TLR2, TLR4, and TLR6 on the production of TNF-alpha, IL-1beta, TLR2, TLR4, and TLR6. These data show that TLR2, TLR4, and TLR6 ligation synergistically stimulates the production of TNF-alpha and IL-1beta in IL-1Ra-deficient mice and suggest that TLRs contribute to the perpetuation of spontaneous arthritis in this animal model.
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PMID:Synergism of toll-like receptor 2 (TLR2), TLR4, and TLR6 ligation on the production of tumor necrosis factor (TNF)-alpha in a spontaneous arthritis animal model of interleukin (IL)-1 receptor antagonist-deficient mice. 1942 61

Cinnamaldehyde (CA) has been known to exhibit anti-inflammatory and anticancer effects. Although numerous pharmacological effects have been demonstrated, regulatory effect of CA on the functional activation of monocytes and macrophages has not been fully elucidated yet. To evaluate its monocyte/macrophage-mediated immune responses, macrophages activated by lipopolysaccharide (LPS), and monocytes treated with proaggregative antibodies, and extracellular matrix protein fibronectin were employed. CA was able to suppress both the production of nitric oxide (NO) and upregulation of surface levels of costimulatory molecules (CD80 and CD69) and pattern recognition receptors (toll-like receptor 2 (TLR2) and complement receptor (CR3)). In addition, CA also blocked cell-cell adhesion induced by the activation of CD29 and CD43 but not cell-fibronectin adhesion. Immunoblotting analysis suggested that CA inhibition was due to the inhibition of phosphoinositide-3-kinase (PI3K) and phosphoinositide-dependent kinase (PDK)1 as well as nuclear factor-(NF-) kappaB activation. In particular, thiol compounds with sulphydryl group, L-cysteine and dithiothreitol (DTT), strongly abrogated CA-mediated NO production and NF-kappaB activation. Therefore, our results suggest that CA can act as a strong regulator of monocyte/macrophage-mediated immune responses by thiolation of target cysteine residues in PI3K or PDK1.
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PMID:Regulatory effect of cinnamaldehyde on monocyte/macrophage-mediated inflammatory responses. 2046 61

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