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)

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are critical for cellular responses to a variety of bacterial, viral, and fungal products. Mast cells are important to host survival in a number of models of bacterial infection and might act as sentinel cells in host defense. We therefore examined the expression of TLRs and associated molecules by murine bone marrow-derived mast cells (BMMCs). BMMCs and the murine mast cell line MC/9 expressed mRNA for TLR2, TLR4, and TLR6 but not TLR5 and for both adapter molecule MD-2 and signaling molecule MyD88 but lacked surface CD14. After activation with the TLR2- and TLR4-dependent stimuli Staphylococcus aureus-derived peptidoglycan and Escherichia coli-derived lipopolysaccharide (LPS), respectively, mast cells produced significant levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). To determine whether mast cells require TLR4 for cellular responses to LPS, mast cells were derived from the bone marrow cells of C3H/HeJ and C57Bl/10ScNCr mice containing a point mutation and a null mutation, respectively, in TLR4. Using these models, we demonstrated that the BMMC IL-6 and TNF-alpha responses to LPS were completely dependent on functional TLR4 with no significant LPS response observed in its absence. These findings have important implications for the mechanism of mast cell responses to pathogens and their products and suggest that different TLR4-expressing cells might have different thresholds for activation with LPS.
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PMID:Toll-like receptor 4-mediated activation of murine mast cells. 1173 61

Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.
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PMID:Negative regulation of toll-like receptor-mediated signaling by Tollip. 1175 56

Much research has focused on the responses to microbial products of immune cells such as monocytes, macrophages, and neutrophils. Although the liver is a primary response organ in various infections, relatively little is known about the antimicrobial responses of its major cell type, the hepatocyte. It is now known that the recognition of bacteria occurs via cell-surface proteins that are members of the Toll-like receptor (TLR) family. In addition, lipopolysaccharide (LPS) is bound by circulating LPS-binding protein (LBP) and presented to cell-surface CD14, which in turn interacts with TLR and transduces an intracellular signal. We investigated the CD14 and TLR2 responses of whole liver and isolated hepatocytes, and demonstrated that these cells can be induced to express the molecules necessary for responses to both Gram-positive and Gram-negative bacteria. Our findings may have clinical implications for pathological states such as sepsis.
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PMID:The hepatocyte as a microbial product-responsive cell. 1175 5

Commensal-associated molecular patterns, the major products of nonpathogenic bacteria, are present at high concentrations at the apical surface of the intestinal epithelium. However, the nature of the interaction of commensal-associated molecular patterns with the lumenal surface of the epithelium has not been defined. We have recently demonstrated that intestinal epithelial cells constitutively express several Toll-like receptors (TLRs) in vitro and in vivo that seem to be the key receptors responsible for immune cell activation in response to various bacterial products. In this study we characterize the subcellular distribution of two major TLRs, TLR2 and TLR4, and their ligand-specific dynamic regulation in the model human intestinal epithelial cell line T84. Immunocytochemical studies indicate that TLR2 and TLR4 are constitutively expressed at the apical pole of differentiated T84 cells. After stimulation with lipopolysaccharide or peptidoglycan, TLRs selectively traffic to cytoplasmic compartments near the basolateral membrane. Thus, we demonstrate that TLRs are positioned at the apical pole where they are poised to monitor the sensitive balance of the lumenal microbial array. The results of this dynamic epithelial surveillance can then be conveyed to the underlying cell populations of the lamina propria via these innate immune pattern recognition receptors.
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PMID:Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. 1178 10

Macrophages form a crucial bridge between the innate and adaptive immune response. One of their most important functions is to recognize infectious microorganisms. Toll-like receptors (TLRs) are key elements in pathogen recognition, and among them, TLR2 and TLR4 are most discussed. However, expression patterns of TLRs during myeloid cell differentiation to macrophage are unknown. In this study, we examined differentiation in the model human myeloid cell line, HL-60, treated with phorbol 12-myristate 13-acetate (PMA) or VitD(3). Expression of TLR2, TLR4, and CD14 were measured by reverse transcription-PCR, RNase protection assay, and fluorescence-activated cell sorter assays. After treatment by PMA (1, 10, and 100 nM) for 12, 24, and 48 h, expression of TLR2 and CD14 mRNA was increased in a time- and dose-dependent manner. However, VitD(3) only induced expression of CD14 but not TLR2 in HL-60 cells. TLR4 was expressed constitutively before differentiation and increased slightly after that. Thus, PMA-mediated differentiation of HL-60 cells to macrophages is associated largely with TLR2 expression and, to a much lesser extent, with TLR4. Furthermore, up-regulation of TLR2 and CD14 mRNA expression by PMA was abrogated by a protein kinase C inhibitor, Calphostine C, suggesting the up-regulation of TLR2 and CD14 mRNA is dependent on the activation of protein kinase C. Coexpression of CD14/TLR2 and/or CD14/TLR4 may be essential but not sufficient for the production of tumor necrosis factor-alpha in response to lipopolysaccharide in our system.
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PMID:Expression of toll-like receptors 2 and 4 and CD14 during differentiation of HL-60 cells induced by phorbol 12-myristate 13-acetate and 1 alpha, 25-dihydroxy-vitamin D(3). 1180 29

Gamma interferon (IFN-gamma)-primed human gingival fibroblasts (HGF) have been shown to produce higher levels of interleukin-8 (IL-8) upon stimulation with bacterial products and inflammatory cytokines than nonprimed controls. In this study, we examined whether priming of HGF with IFN-gamma up-regulates IL-8 production by the cells in response to purified lipopolysaccharide (LPS). The priming effect of IFN-gamma was clearly observed in the high-CD14-expressing (CD14(high)) HGF but not in the low-CD14-expressing (CD14(low)) HGF. The CD14(high) HGF were most effectively primed with IFN-gamma (1,000 IU/ml) for 72 h. To elucidate the mechanism of the priming effects of IFN-gamma for the LPS response by HGF, we examined whether IFN-gamma regulated expression of CD14, Toll-like receptor 2 (TLR2), TLR4, MD-2, and MyD88, all of which are molecules suggested to be associated with LPS signaling. In CD14(high) HGF, IFN-gamma markedly up-regulated CD14 and MyD88 but not TLR4 protein and MD-2 mRNA expression, while in CD14(low) HGF, IFN-gamma slightly increased MyD88 and scarcely affected CD14, TLR4 protein, and MD-2 mRNA levels. LPS-induced IL-8 production by IFN-gamma-primed CD14(high) HGF was significantly inhibited by monoclonal antibodies (MAbs) against CD14 and TLR4, but not by an anti-TLR2 MAb. These findings suggested that IFN-gamma primed CD14(high) HGF to enhance production of IL-8 in response to LPS through augmentation of the CD14-TLR system, where the presence of membrane CD14 was indispensable for the response of HGF to LPS.
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PMID:Human gingival CD14(+) fibroblasts primed with gamma interferon increase production of interleukin-8 in response to lipopolysaccharide through up-regulation of membrane CD14 and MyD88 mRNA expression. 1185 10

Innate immune response in Drosophila is mediated by signaling through Toll receptors. In mammals, Toll-like receptors (TLRs), comprising a large family, recognize a specific pattern of microbial components. So far, the roles of TLR2, TLR4, TLR5, TLR6, and TLR9 have been revealed. The recognition of microbial components by TLRs leads to activation of innate immunity, which provokes inflammatory responses and finally the development of adaptive immunity. The inflammatory response depends on a TLR-mediated MyD88-dependent cascade. However, there seems to exist additional cascades in TLR signaling. In the case of TLR4 signaling, an MyD88-independent pathway is now being characterized. In addition to the activation of innate immune responses, TLR-mediated signaling leads to suppression of the activity of innate immune cells, represented by "lipopolysaccharide (LPS) tolerance". Progress in elucidating the molecular mechanisms for LPS tolerance has been made through the analysis of TLR-mediated signaling pathways. Thus, the activity for innate immune responses is known to be finely regulated by TLRs.
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PMID:Regulation of innate immune responses by Toll-like receptors. 1186 2

Early events in the response of cells to lipopolysaccharide (LPS) include activation of NF-kappaB and stress-activated MAP kinase p38. Recent studies have shown that the human Toll-like receptor 2 (TLR2) mediates activation of NF-kappaB in response to commercial preparations of LPS (comLPS), membrane lipoproteins, and Gram-positive bacterial products. Here, we show that expression of TLR2 in human embryonic kidney 293 cells enabled p38 phosphorylation in response to comLPS, a synthetic bacterial lipoprotein, and B. subtilis. Activation of p38 was confirmed by an in vitro kinase assay using ATF2 as substrate and by an assay measuring activation of the downstream effector of p38, MAP kinase-activated protein kinase in cells. Thus, TLR2 initiated the signaling pathway for p38 in response to bacterial products.
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PMID:Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. 1186 88

Toll-like receptors (TLRs) are important signal transducers that mediate inflammatory reactions induced by microbes through pattern recognition of virulence molecules such as lipopolysaccharide (LPS) and lipoproteins. We investigated whether proinflammatory cytokine responses induced by certain bacterial protein adhesins may also depend on TLRs. In differentiated THP-1 mononuclear cells stimulated by LPS-free recombinant fimbrillin (rFimA) from Porphyromonas gingivalis, cytokine release was abrogated by monoclonal antibodies (MAbs) to CD14 and TLR4 but not to TLR2. Similar experiments using anti-beta2 integrin MAbs suggested that beta2 integrins (CD11/CD18) also play a role in cytokine induction by rFimA or native fimbriae. Minor fimbriae (distinct from the fimA-encoded major fimbriae) of P. gingivalis induced proinflammatory cytokine release in a CD14- and TLR2-dependent mode. Cytokine induction by BspA, a leucine-rich repeat protein from Bacteroides forsythus, depended heavily on CD14 and TLR2. We also found that the ability of the streptococcal protein AgI/II to stimulate cytokine release depended partially on CD14 and TLR4, and the AgI/II segment that possibly interacts with these receptors was identified as its N-terminal saliva-binding region. When THP-1 cells were exposed to rFimA for 24 h, surface expression of CD14 and CD18 was decreased and the cells became hyporesponsive to cytokine induction by a second challenge with rFimA. However, tolerance induction was abolished when the THP-1 cells were pretreated with rFimA in the presence of either anti-CD14 MAb or anti-TLR4 MAb. Induction of cross-tolerance between rFimA and LPS correlated with downregulation of the pattern recognition receptors involved. Our data suggest that the CD14-TLR2/4 system is involved in cytokine production and tolerance induction upon interaction with certain proinflammatory bacterial protein adhesins.
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PMID:Dependence of bacterial protein adhesins on toll-like receptors for proinflammatory cytokine induction. 1187 86

Treatment of macrophages with lipopolysaccharide (LPS) from Gram-negative bacteria or peptidoglycan (PGN) from Gram-positive bacteria activates multiple intracellular signaling pathways and a large, diverse group of nuclear transcription factors. The signaling receptors for PGN and LPS are now known to be the Toll-like receptors 2 and 4 (TLR2 and -4, respectively). While a large body of literature indicates that the members of the TLR family activate nearly identical cytoplasmic signaling programs, several recent reports have suggested that the functional outcomes of signaling via TLR2 or TLR4 are not equivalent. In the current studies, we compared the responses of the secretory IL-1 receptor antagonist (sIL-1Ra) gene to both LPS and PGN. Both LPS and PGN induced IL-1Ra gene expression; however, the combination of both stimuli synergistically increased sIL-1Ra mRNA expression and promoter activity, suggesting that the signals induced by PGN and LPS are not equivalent. While both LPS and PGN utilized the PU.1-binding sites in the proximal sIL-1Ra promoter region to generate a full response, additional distinct promoter elements were utilized by LPS or PGN. Activation of p38 stress-activated protein kinase was required for LPS- or PGN-induced IL-1Ra gene expression, but the p38-responsive promoter elements localized to distinct regions of the sIL-1Ra gene. Additionally, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. Collectively, these data indicated that while some of the intracellular signaling events by TLR2 and TLR4 agonists are similar, there are clearly distinct differences in the responses elicited by these two bacterial products.
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PMID:Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages. 1187 29


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