UNIPROT:P43026 - FACTA Search

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)

The presence of a novel 38 kDa protein that is tyrosine phosphorylated in human neutrophils, a terminally differentiated cell, upon stimulation of these cells with low concentrations of lipopolysaccharide (LPS) in combination with serum has been demonstrated. This 38 kDa protein was identified as the mammalian homologue of HOG1 in yeast, the p38 mitogen-activated protein (MAP) kinase. This conclusion is based on the experimental findings that anti-phosphotyrosine (anti-PY) antibody immunoprecipitates a 38 kDa protein that is recognized by anti-p38 MAP kinase antibody, and conversely, anti-p38 MAP kinase antibody immunoprecipitates a 38 kDa protein that can be recognized by anti-PY antibody. Moreover, this tyrosine phosphorylated protein is found associated entirely with the cytosol. It was also found that this p38 MAP kinase is activated following stimulation of these cells with low concentrations of LPS in combination with serum. This conclusion is based on three experimental findings. First, soluble fractions isolated from LPS-stimulated cells phosphorylate heat shock protein 27 (hsp27) in an in vitro assay, and this effect is not inhibited by protein kinase C and protein kinase A inhibitor peptides. This effect is similar to the effect produced by the commercially available phosphorylated and activated MAPKAP kinase-2 (MAP kinase activated protein kinase-2). Secondly, a 27 kDa protein that aligns with a protein recognized by anti-hsp27 antibody is phosphorylated upon LPS stimulation of intact human neutrophils prelabelled with radioactive phosphate. Lastly, immune complex protein kinase assays, using [gamma-32P]ATP and activating transcription factor 2 (ATF2) as substrates, showed increased p38 MAP kinase activity from LPS-stimulated human neutrophils. The phosphorylation and activation of this p38 MAP kinase can be affected by both G-protein-coupled receptors such as platelet-activating factor (PAF) and non-G-protein-coupled receptors such as the cytokine-coupled receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha). The effect of low concentrations of PAF is greatly increased in cells pretreated with LPS. The tyrosine phosphorylation of the p38 MAP kinase is not restricted to stimuli that mediate their actions through membrane-associated receptors, but it can be affected by agents that bypass membrane-associated receptors such as the protein translation blocker anisomycin. While anisomycin is known to increase the tyrosine phosphorylation of the 54 kDa SAPK (stress-activated protein kinase), this is the first report that shows that anisomycin also tyrosine phosphorylates the p38 MAP kinase. Cytokine receptors that increase the tyrosine phosphorylation and activation of the erk1 and erk2 MAP kinases have less effect on this p38 MAP kinase than those that do not affect the erk1 and erk2 MAP kinases. The possible role of the p38 MAP kinase in the phosphorylation of cytosolic phospholipase A2 is discussed.
...
PMID:Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists. 876 79

The expression of E-selectin induced by tumor necrosis factor (TNF) on the surface of human umbilical vein endothelial cells (HUVEC) was partially inhibited by an increase in the level of adenosine 3',5'-cyclic monophosphate (cAMP), produced by forskolin or cholera toxin combined with the type IV phosphodiesterase inhibitor rolipram and the protein kinase A agonist phosphorothioate analogue of cAMP SpcAMPS. The same agents had no significant effect on the constitutive and TNF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1), whereas the effect on vascular cell adhesion molecule 1 (VCAM-1) expression was variable depending on cell culture conditions. The stimulatory effects of phorbol 12-myristate 13-acetate and bacterial lipopolysaccharide (LPS) on E-selectin expression were also downregulated by the forskolin-rolipram combination and by SpcAMPS. Inhibition of the surface expression of E-selectin was associated with a decrease of the total amount of the protein in the cell lysate and a reduced mRNA level, with no significant effect on mRNA stability. In anesthetized rats, the terbutaline-rolipram combination reduced the rolling of leukocytes induced by LPS in the mesenteric microcirculation. In addition to their partial inhibitory effect on the TNF-induced surface expression of E-selectin on HUVEC, the forskolin-rolipram combination and SpcAMPS strongly inhibited the release of soluble E-selectin from these cells; the release of soluble ICAM-1 and VCAM-1 was unaffected by these agents. Isoproterenol reduced the release of soluble E-selectin, whereas it had no significant effect on the cell surface expression of the protein. This study underscores the potential anti-inflammatory effect of a rise in the endothelial cAMP level.
...
PMID:Action of cAMP on expression and release of adhesion molecules in human endothelial cells. 878 Jan 74

Aging is associated with an increased occurrence of infection and cancer, and, as people age, they begin to exhibit age-related immune deficiencies, collectively termed immunosenescence. To determine the effects of age on human monocytes, 'aged monocytes' (isolated from individuals > or = 65 years of age) were compared with 'young monocytes' (isolated from individuals approximately 25 years of age) for their ability to be activated by lipopolysaccharide. Our results show that aged monocytes display a decrease in their cytotoxicity against tumor cells in vitro, a decrease in interleukin (IL1) secretion (although no decrease in IL1 precursor production was observed), a decrease in reactive oxygen and nitrogen intermediate (ROI/RNI) release, an increase in intracellular levels of cyclic adenosine monophosphate and a loss of protein kinase translocation. Therefore, aged monocytes present distinct characteristics of immunosenescence.
...
PMID:Immunological functions of aged human monocytes. 882 31

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.
...
PMID:1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. 883 59

We studied the effects of endotoxin from Escherichia coli (E. coli) on Ca2+ channel activity in PC12 cells using the cell-attached patch clamp technique. Endotoxin (1-100 ng/ml) decreased channel availability (n x Po) to about one third of control values, an effect that required 3.5 +/- 1 min (mean +/- SD; n = 13) to reach steady state. The biophysical properties of the channel, including slope conductance (22 pS; 40 mM Ba2+), voltage dependence of n x Po, and open times (tau 1 = 0.78 ms, tau 2 = 8.9 ms) for the two open states at 0 mV, were not altered. The effect of endotoxin was blocked by polymyxin-B, indicating involvement of the lipid-A moiety of lipopolysaccharide, and by the tyrosine kinase (tk) inhibitor, tyrphostin. The effect of endotoxin was mimicked by 8-bromo-cGMP (100 microM), and was blocked by the inhibitor of cGMP-dependent protein kinase (PKG), H-8, suggesting involvement of the cGMP/PKG pathway. The effect of endotoxin also was blocked by the nitric oxide (NO) synthase inhibitor, NG-monomethyl-L-arginine monoacetate, suggesting involvement of nitric oxide synthase (NOS). The rapidity of the effect of endotoxin on Ca2+ channel activity suggested that constitutive NOS (cNOS) was involved, in accordance with our finding that endotoxin-induced transcriptional induction of NOS, as measured by nitrite production, required > 6 hr. We conclude that early signaling events by endotoxin in PC12 cells involve tk, cNOS, cGMP/PKG, and Ca2+ channels.
...
PMID:Early signaling events by endotoxin in PC12 cells: involvement of tyrosine kinase, constitutive nitric oxide synthase, cGMP-dependent protein kinase, and Ca2+ channels. 884 82

Ubiquitously expressed SH2-containing tyrosine phosphatases interact physically with tyrosine kinase receptors or their substrates and relay positive mitogenic signals via the activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. Conversely, the structurally related phosphatase SHP-1 is predominantly expressed in hemopoietic cells and becomes tyrosine phosphorylated upon colony-stimulating factor 1 treatment of macrophages without associating with the colony-stimulating factor 1 receptor tyrosine kinase. Mice lacking functional SHP-1 (me/me and me(v)/me(v)) develop systemic autoimmune disease with accumulation of macrophages, suggesting that SHP-1 may be a negative regulator of hemopoietic cell growth. By using macrophages expressing dominant negative Ras and the me(v)/me(v) mouse mutant, we show that SHP-1 is activated in the course of mitogenic signal transduction in a Ras-dependent manner and that its activity is necessary for the Ras-dependent activation of the MAPK pathway but not of the Raf-1 kinase. Consistent with a role for SHP-1 as an intermediate between Ras and the MEK-MAPK pathway, Ras-independent activation of the latter kinases by bacterial lipopolysaccharide occurred normally in me(v)/me(v) cells. Our results sharply accentuate the diversity of signal transduction in mammalian cells, in which the same signaling intermediates can be rearranged to form different pathways.
...
PMID:Involvement of the protein tyrosine phosphatase SHP-1 in Ras-mediated activation of the mitogen-activated protein kinase pathway. 888 25

Catecholamines have been shown to inhibit some aspects of macrophage activation through a beta receptor-dependent mechanism. This study was undertaken to analyze the effects of isoproterenol, a specific beta-adrenergic agonist, on the synthesis of interleukin-10 (IL-10), a major macrophage-deactivating factor. Isoproterenol increased IL-10 release from lipopolysaccharide-(LPS)-activated mouse peritoneal macrophages in a dose-dependent manner. A significant effect was already observed with 1 microM isoproterenol, while a 4.5-fold increase was achieved with 10 microM. This increase was observed only if macrophages were exposed to isoproterenol for at least 2 h before LPS challenge. It was apparent within 0.5 h and persisted through 24 h at all the LPS concentrations used. A similar increase was observed at the IL-10 mRNA level, as judged by enzyme-linked immunosorbent assay-polymerase chain reaction. The macrophage response to isoproterenol that led to cyclic AMP accumulation was markedly inhibited by H-89, a potent inhibitor of protein kinase A. These data suggest the involvement of cyclic AMP in the regulation of IL-10 synthesis by isoproterenol. IL-10 was in turn partly responsible for a reduction in tumor necrosis factor-alpha synthesis. In vivo, the administration of oxprenolol, a beta-receptor antagonist, significantly reduced serum IL-10 levels 90 min after LPS challenge. Thus, the present study provides the first evidence that endogenous catecholamines are of critical importance in determining the magnitude of the IL-10 response in experimental endotoxemia.
...
PMID:Regulation of interleukin-10 production by beta-adrenergic agonists. 892 45

To determine the relevance of mitogen-activated protein kinase activity to macrophage proliferation, we measured the stimulation of myelin basic protein (MBP) kinase and extracellular signal-related protein kinase (ERK) activity in a macrophage cell line (BAC1.2F5), bone marrow-derived macrophages (BMM) and resident peritoneal macrophages (RPM). By using an 'ingel' MBP kinase assay the activities of renaturable MBP kinases were detected, including several with molecular masses similar to those of ERK-1 and ERK-2. These represented a minor fraction of total activity and were not activated to an appreciable extent by colony-stimulating factor 1 (CSF-1). By using a sensitive and specific immune-complex kinase assay, activation of ERK-1 by CSF-1 and lipopolysaccharide (LPS) was demonstrated. Two kinetically distinct pathways of ERK-1 activation by CSF-1 were resolved, with peak activations occurring at 5 and 15 min. The kinetics and degree of activation were similar in BMM, BAC1.2F5 cells and RPM. LPS activated ERK-1 with a single peak at 10-15 min, corresponding to the later peak of activation by CSF-1. Thus there was no strict correlation between ERK activation and macrophage proliferation.
...
PMID:Differences in the kinetics of activation of protein kinases and extracellular signal-related protein kinase 1 in colony-stimulating factor 1-stimulated and lipopolysaccharide-stimulated macrophages. 900 93

Nitric oxide produced by inducible nitric-oxide synthase (iNOS) in different brain cells in response to various cytokines plays an important role in the pathophysiology of stroke and other neurodegenerative diseases. This study underlines the importance of cAMP in inhibiting the induction of NO production by lipopolysaccharide (LPS) and cytokines in rat primary astrocytes. Compounds (forskolin, 8-bromo-cAMP, and (Sp)-cAMP) that increase cAMP and activate protein kinase A (PKA) were found to inhibit LPS- and cytokine-mediated production of NO as well as the expression of iNOS, whereas compounds (H-89 and (Rp)-cAMP) that decrease cAMP and PKA activity stimulated the production of NO and the expression of iNOS in rat primary astrocytes. Forskolin, but not the inactive analogue 1,9-dideoxyforskolin, inhibited NO production and iNOS expression in a dose-dependent manner in astrocytes. The inhibition of LPS- and/or cytokine-induced NO production in rat C6 glial cells by forskolin suggest that similar to astrocytes, iNOS expression in C6 cells is also regulated by similar mechanisms. In contrast, in rat peritoneal macrophages the cAMP analogues stimulated the LPS- and cytokine-induced production of NO. In vitro, the PKA had no effect on iNOS activity in LPS-treated astrocytes or macrophages, suggesting that PKA modulates the intracellular signaling events associated with the induction of iNOS biogenesis rather than the post-translational modification of iNOS. The compounds which activate PKA activity, blocked the activation of NF-kappabeta in astrocytes but stimulated the activation of NF-kappabeta in macrophages. This differential regulation of NF-kappabeta activation in two different cell types (astrocytes and macrophages) by the same second messenger (cAMP) indicates that intracellular events or pathways in the activation of NF-kappabeta may be different. Moreover, this inhibition of iNOS expression in LPS- and cytokine-treated astrocytes by cAMP may be of therapeutic potential in NO-mediated cytotoxicity in neurodegenerative diseases.
...
PMID:Increasing cAMP attenuates induction of inducible nitric-oxide synthase in rat primary astrocytes. 906 41

Apoptosis occurs in response to different cellular stresses, including viral infection, inflammatory cytokines, growth factor deprivation, and UV light, but it is unclear whether these inducers share a common mechanism of induction. The interferon-induced, double-stranded RNA-activated protein kinase (PKR) has been implicated in processes that rely on apoptosis as control mechanisms in vivo, including antiviral activities, cell growth regulation, and tumorigenesis. Here we report that mouse embryo fibroblasts from mutant mice containing homozygous deletions in the PKR gene (Pkr(0/0) mice) were resistant to apoptotic cell death in response to double-stranded RNA, tumor necrosis factor-alpha, or lipopolysaccharide. The mechanism underlying the suppression of apoptosis in the Pkr(0/0) cells could be attributed to defects in the activation of DNA-binding activity for the transcription factor interferon regulatory factor-1 and in Fas mRNA induction. Thus, these results provide genetic evidence implicating a requirement for PKR in mediating different forms of stress-related apoptosis.
...
PMID:A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. 909 84

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>