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)

Engagement of many cell surface receptors results in tyrosine phosphorylation of an overlapping set of protein substrates. Some proteins, such as the adaptor protein Shc, and a frequently observed Shc-associated protein, p145, are common substrates in a variety of receptor signaling pathways and are thus of special interest. Tyrosine-phosphorylated Shc and p145 coprecipitated with anti-Shc antibodies following B cell antigen receptor (BCR) cross-linking or interleukin-4 (IL-4) receptor activation in B cells, and after lipopolysaccharide (LPS) treatment or IgG Fc receptor (Fc gamma R) cross-linking in macrophages. In the case of BCR stimulation, we have shown that this represented the formation of an inducible complex. Furthermore, in response to LPS activation or Fc gamma R cross-linking of macrophages and BCR cross-linking (but not IL-4 treatment) of B cells, we observed a similar tyrosine-phosphorylated p145 protein associated with the tyrosine kinase Syk. We did not detect any Shc associated with Syk, indicating that a trimolecular complex of Shc, Syk, and p145 was not formed in significant amounts. By several criteria, the Syk-associated p145 was very likely the same protein as the previously identified Shc-associated p145. The Syk-associated p145 and the Shc-associated p145 exhibited identical mobility by SDS-polyacrylamide gel electrophoresis and identical patterns of induced tyrosine phosphorylation. The p145 protein that coprecipitated with either Shc or Syk bound to a GST-Shc fusion protein. In addition, a monoclonal antibody developed against Shc-associated p145 also immunoblotted the Syk-associated p145. The observations that p145 associated with both Shc and Syk proteins, in response to stimulation of a variety of receptors, suggest that it plays an important role in coordinating early signaling events.
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PMID:Activation-induced association of a 145-kDa tyrosine-phosphorylated protein with Shc and Syk in B lymphocytes and macrophages. 855 43

Vascular endothelial cells (EC) are primary cellular targets for the actions of pro-inflammatory cytokines such as tumor necrosis factor (TNF). We have studied the signaling pathways used by TNF that lead to new gene expression (endothelial cell activation) or apoptosis (endothelial cell injury). Both responses are initiated by ligand binding to TNFR-I (the p55 receptor). TNF initiates transcription of the E-selectin gene by activation of the transcription factors NF-kappa B and c-Jun/ATF-2. NF-kappa B is activated following degradation of I kappa B alpha and I kappa B-beta. Activation of c-Jun/ATF-2 involves new c-Jun synthesis, and more importantly, phosphorylation of the amino terminus of c-Jun by Jun N-terminal kinase (JNK). Studies in transiently transfected human umbilical vein endothelial cells have revealed that NF-kappa B activation is initiated through the adaptor protein TRAF-2. The activation of JNK also depends upon TRAF-2 and probably involves a kinase cascade initiated by the small G proteins Rac-1 and/or cdc-42. Normally, TNF does not injure human EC. However, TNF can cause apoptosis of EC when cells are co-treated with either the protein synthesis inhibitor cycloheximide (CHX) or the lipid mediator ceramide (cer). The pathways leading to apoptosis following treatment with TNF + CHX and TNF + cer are different since only TNF + CHX is blocked by the caspase inhibitors crmA protein or the peptide zVAD.fmk while only TNF + cer is blocked by the anti apoptotic proteins Bcl-2, Bcl-XL or Al. Both pathways may be inhibited by the anti-apoptotic protein A-20. TNF does not cause the liberation of cer in EC, perhaps because of limited expression of neutral sphingomyelinase-activating adaptor protein FAN. These observations suggest that TNF normally acts as an activator of EC but may change from an activator to a killer of EC when combined with agents that release ceramide, such as u.v. irradiation or cytotoxic drugs, or with ceramide mimetics such as lipopolysaccharide. The activation and injury of endothelial cells induced by TNF and other proinflammatory cytokines may underlie the local effects of these mediators in vivo.
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PMID:Activation and injury of endothelial cells by cytokines. 976 10

MyD88 is a general adaptor protein that plays an important role in the Toll/IL-1 receptor family signalings. Recently, Toll-like receptors 2 and 4 (TLR2 and TLR4) have been suggested to be the signaling receptors for lipopolysaccharide (LPS). In this study, we demonstrate that MyD88 knockout mice lack the ability to respond to LPS as measured by shock response, B cell proliferative response, and secretion of cytokines by macrophages and embryonic fibroblasts. However, activation of neither NF-kappaB nor the mitogen-activated protein (MAP) kinase family is abolished in MyD88 knockout mice. These findings demonstrate that signaling via MyD88 is essential for LPS response, but the inability of MyD88 knockout mice to induce LPS-dependent gene expression cannot simply be attributed to lack of the activation of MAP kinases and NF-kappaB.
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PMID:Unresponsiveness of MyD88-deficient mice to endotoxin. 1043 84

Lipocortin 1 (annexin 1) is a calcium- and phospholipid-binding protein that modulates anti-inflammatory responses including those induced by lipopolysaccharide. To investigate the precise role of lipocortin 1 in regulating the lipopolysaccharide-induced signal transduction pathways, we generated stable RAW 264.7 macrophage cell lines expressing decreased and increased lipocortin 1 protein. Several RAW 264.7 clones with increased lipocortin 1 protein levels showed constitutive activation of the mitogen-activated protein kinase extracellular signal-regulated kinase, which was down-regulated following lipopolysaccharide treatment. Conversely, clones with decreased lipocortin 1 protein expression showed prolonged extracellular signal-regulated kinase activity, following lipopolysaccharide activation. Lipocortin 1 specifically regulates the components of the extracellular signal-regulated kinase pathway, since changes in lipocortin 1 protein expression had no affect on the related mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Lipocortin 1 modulated upstream components of the extracellular signal-regulated kinase pathway and associated with the adaptor protein growth factor binding protein. The downstream consequences of altered extracellular signal-regulated kinase activity were independent of the proinflammatory transcription factor nuclear factor kappa B. These data indicate that lipocortin 1 specifically regulates proximal signaling components of the extracellular signal-regulated kinase signal transduction pathway, resulting in the modulation of biochemical functions in RAW macrophages.
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PMID:The annexin protein lipocortin 1 regulates the MAPK/ERK pathway. 1060 17

B cell antigen receptor signals development, activation, proliferation, or apoptosis of B cells depending on their condition, and its proper signaling is critical for activation and homeostasis of the immune system. The B cell-restricted adaptor protein BASH (also termed BLNK/SLP-65) is rapidly phosphorylated by the tyrosine kinase Syk after BCR ligation and binds to various signaling proteins. BASH structurally resembles SLP-76, which is essential for T cell development and T cell receptor signaling. To evaluate the role for BASH in B cell development and function in vivo, we disrupted BASH alleles in embryonic stem cells by means of homologous recombination and used these cells to complement lymphocyte-incompetent blastocysts from RAG2-deficient mice. In the resultant chimeric mice, T cell development was apparently normal, but B cell development was impaired, and a normally rare population of large preB cells expressing preB cell receptor dominated in the bone marrow in place of small preB cells, although they were mostly noncycling. In addition, the mature B cell populations in the periphery and the bone marrow profoundly decreased in size, as did B-1 cells in the peritoneal cavity, and serum Ig was severely reduced. The BASH-deficient B cells scarcely proliferated or up-regulated B7-2 in response to BCR ligation and poorly proliferated upon CD40 ligation or lipopolysaccharide stimulation. This phenotype indicates that BASH is critical for preB cell receptor signaling inducing proliferation of large preB cells and the following differentiation, for peripheral B cell maturation, and for BCR signaling inducing activation/proliferation of B cells.
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PMID:The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells. 1068 1

Interleukin-1 receptor-associated kinase (IRAK), a signal transducer for interleukin-1, has also been suggested to participate in the Toll-like receptor-mediated innate immune response to bacterial endotoxin lipopolysaccharide (LPS). Using the human promonocytic THP-1 cell line, we demonstrated that the endogenous IRAK is quickly activated in response to bacterial LPS stimulation, as measured by its in vitro kinase activity toward myelin basic protein. LPS also triggers the association of IRAK with MyD88, the adaptor protein linking IRAK to the Toll-like receptor/interleukin-1beta receptor intracellular domain. Macrophage cells with prolonged LPS treatment become tolerant to additional dose of LPS and no longer express inflammatory cytokines. Endotoxin tolerance is a common phenomenon observed in blood from sepsis patients. We observed for the first time that the quantity of IRAK is greatly reduced in LPS-tolerant THP-1 cells, and its activity no longer responds to further LPS challenge. In addition, IRAK does not associate with MyD88 in the tolerant cells. Furthermore, application of AG126, a putative tyrosine kinase inhibitor, can substantially alleviate the LPS-induced cytokine gene expression and can also decrease IRAK level and activity. Our study indicates that IRAK is essential for LPS-mediated signaling and that cells may develop endotoxin tolerance by down-regulating IRAK.
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PMID:Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. 1081 44

The innate immune system evolved to recognize conserved microbial products, termed pathogen-associated molecular patterns (PAMPs), which are invariant among diverse groups of microorganisms. PAMPs are recognized by a set of germ-line encoded pattern recognition receptors (PRRs). Among the best characterized PAMPs are bacterial lipopolysaccharide (LPS), peptidoglycan (PGN), mannans, and other constituents of bacterial and fungal cell walls, as well as bacterial DNA. Recognition of bacterial DNA is the most enigmatic of these, as it depends on a particular sequence motif, called the CpG motif, in which an unmethylated CpG present in a particular sequence context accounts for a potent immunostimulatory activity of CpG DNA. Receptor(s) of the innate immune system that mediate recognition of CpG DNA are currently unknown. Here, we report that recognition of CpG DNA requires MyD88, an adaptor protein involved in signal transduction by the Toll-like receptors (TLRs), essential components of innate immune recognition in both Drosophila and mammals [1,2]. Signaling induced by CpG DNA was found to be unaffected in cells deficient in TLR2 or TLR4, suggesting that some other member of the Toll family mediates recognition of bacterial DNA.
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PMID:Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. 1099 97

The recent characterization of human homologs of Toll may be the missing link for the transduction events leading to nuclear factor-kappaB (NF-kappaB) activity and proinflammatory gene transcription during innate immune response. Mammalian cells may express as many as 10 distinct Toll-like receptors (TLRs), although TLR2 is a key receptor for recognizing cell wall components of Gram-positive bacteria. The present study investigated the effects of circulating bacterial cell wall components on the expression of the gene-encoding TLR2 across the mouse brain. Surprisingly, while Gram-negative components caused a robust increase in TLR2 transcription within the cerebral tissue, peptidoglycan (PGN) and lipoteichoic acid (LTA), either alone or combined, failed to modulate the receptor transcript. Indeed, the mRNA levels for TLR2 in the choroid plexus and few other regions of the brain remained similar between vehicle-, LTA-, PGN-, and LTA/PGN-administered mice at all the times evaluated (i.e. 30 min to 24 h post-intraperitoneal injection). This contrasts with the profound de novo expression of TLR2 following a single systemic injection of the lipopolysaccharide (LPS). The signal was first detected in regions devoid of blood-brain barrier and few blood vessels and microcapillaries. A second wave of TLR2 expression was also detected from these structures to their surrounding parenchymal cells that stained for a microglial marker iba1. The rapid induction of IkappaBalpha (index of NF-kappaB activity) and up-regulation of the adaptor protein MyD88 suggest that LPS-induced TLR2 transcription may be dependent on the NF-kappaB pathway. These data provide the evidence that TLR2 is not only present in the brain, but its encoding gene is regulated by cell wall components derived from Gram-negative, not Gram-positive, bacteria. The robust wave of TLR2-expressing microglial cells may have a determinant impact on the innate immune response that occurs in the brain during systemic infection by Gram-negative, not Gram-positive, bacteria.
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PMID:Circulating cell wall components derived from gram-negative, not gram-positive, bacteria cause a profound induction of the gene-encoding Toll-like receptor 2 in the CNS. 1170 68

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

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.
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PMID:Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. 1244 41


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