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 immunoglobulin kappa light chain enhancer, kappa B, is an important cis-acting transcriptional element. kappa B binds a number of proteins including the members of the ubiquitous NF-kappa B family of transcription factors. Agarose beads coupled to a double-stranded oligonucleotide containing the kappa B motif were used to isolate a 65-kDa predominantly nuclear phosphoprotein. Southwestern blot analysis demonstrated that this phosphoprotein can bind the kappa B element directly and specifically. This kappa B-associated protein was phosphorylated in vivo and in vitro by a nuclear serine/threonine kinase(s) which, in a number of different cell lines, appeared to be stimulated in response to interleukin-1 alpha and lipopolysaccharide treatment. In the B cell lines 70Z/3 and CH12 LX2B, and the T cell line EL-4 6.1 C10 the activity of the kappa B-associated kinase(s) correlated with the binding activity of nuclear NF-kappa B displayed in a gel shift assay. In vitro, the 65-kDa protein was phosphorylated in the absence of exogenously added kinase. The 65-kDa phosphoprotein and the kinase activity remained associated following sequential anion-exchange and hydrophobic interaction chromatography. These results suggest that the kappa B-associated phosphoprotein is either autophosphorylated or is phosphorylated by a closely associated kinase(s). Stimulation of a nuclear protein kinase which is closely associated with a sequence-specific DNA may reflect a novel mechanism by which growth factors regulate gene expression.
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PMID:A serine/threonine kinase activity is closely associated with a 65-kDa phosphoprotein specifically recognized by the kappa B enhancer element. 182 60

Certain bacterial species, of which we selected Fusobacterium nucleatum, Gardnerella vaginalis, Peptostreptococcus anaerobius and Propionibacterium acnes, were found to induce release of arachidonic acid in a dose- and time-dependent manner in mouse macrophages. The release of arachidonic acid showed a characteristic lag period of approximately 10 min and was accompanied by selective transformation into prostaglandin E2. Bacteria killed by various methods caused a similar response, indicating that bacterial surface structures rather than secreted products were involved. Down-regulation of protein kinase C by treatment of macrophages with 4 beta-phorbol 12-myristate 13-acetate hardly affected the response to bacteria at all, except for a partial inhibition in the case of P. acnes. Furthermore, the generation of prostaglandin E2 was synergistically enhanced when macrophages were exposed to both bacteria and phorbol ester. It is also unlikely that bacterial activation was mediated exclusively via a rise in cytosolic [Ca2+], since bacteria stimulated the release of arachidonic acid also when [Ca2+] was clamped at various levels and since the response to bacteria was enhanced in an additive to synergistic manner when combined with calcium ionophore. Changes in protein phosphorylation in macrophages exposed to F. nucleatum (Gram-negative) were virtually identical to those seen with bacterial lipopolysaccharide, while P. anaerobius (Gram-positive) induced enhanced labeling of a single detectable phosphoprotein. In both cases, the changes in protein phosphorylation showed a time lag of 4-8 min and occurred independently of protein kinase C, consistent with a possible role in signal transduction. These results demonstrate that certain bacteria cause activation of arachidonic acid release and prostaglandin E2 formation in mouse macrophages; that the response is independent of protein kinase C and that it is not wholly mediated via a rise in cytosolic [Ca2+].
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PMID:Protein-kinase-C-independent activation of arachidonate release and prostaglandin E2 formation in macrophages interacting with certain bacteria. 191 41

Mouse peritoneal macrophages respond to activators of protein kinase C and to zymosan particles and calcium ionophore by rapid enhancement of a phospholipase A pathway and mobilization of arachidonic acid. The pattern of protein phosphorylation induced in these cells by 4 beta-phorbol 12-myristate 13-acetate (PMA), 1,2-dioctanoyl-sn-glycerol, exogenous phospholipase C and by zymosan and ionophore A23187 was found to be virtually identical. The time course of phosphorylation differed among the phosphoprotein bands and in only some of those identified (i.e., those of 45 and 65 kDa) was the phosphorylation sufficiently rapid to be involved in the activation of the phospholipase A pathway. Phosphorylation of lipocortin I or II could not be detected. Down-regulation of kinase C by a 24-h pretreatment with PMA resulted in extensive inhibition of both protein phosphorylation and the mobilization of arachidonic acid in response to PMA or dioctanoylglycerol. The phosphorylation of the 45 kDa protein in response to zymosan and A23187 was also inhibited by pretreatment with PMA, while only arachidonic acid release induced by zymosan was inhibited by this pretreatment. Depletion of intracellular calcium had little effect on kinase C-dependent phosphorylation, although arachidonic acid mobilization is severely inhibited under these conditions. Bacterial lipopolysaccharide and lipid A induced a phosphorylation pattern different from that induced by PMA, and down-regulation of protein kinase C did not affect lipopolysaccharide-induced protein phosphorylation. The results indicate (i) that protein kinase C plays a critical role also in zymosan-induced activation of the phospholipase A pathway mobilizing arachidonic acid; (ii) that such activation requires calcium at some step distal to kinase C-mediated phosphorylation and (iii) that phosphorylation of lipocortins does not explain the kinase C-dependent activation.
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PMID:A role for protein kinase C-mediated phosphorylation in the mobilization of arachidonic acid in mouse macrophages. 249 91

Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor on U937 cells results in rapid and TNF dose-dependent phosphorylation of a cytosolic protein with an apparent molecular mass of 26,000 kDa (p26) and an isoelectric point of 5.6. Half-maximal phosphorylation of p26 was achieved at concentrations of 1.8 ng/ml and was detectable within 20 s of TNF-alpha treatment. p26 is phosphorylated exclusively at serine residues. p26 phosphorylation occurs at 37 degrees C as well as at 14 degrees C, indicating that internalization of the TNF receptor is not required for serine kinase activation. Dephosphorylation of p26 starts 10 min after TNF-induced phosphorylation, suggesting a possible regulatory function of this cytosolic protein within the post-TNF receptor signaling system. p26 is also phosphorylated upon treatment with lymphotoxin. In contrast, both interferon-gamma and lipopolysaccharide fail to induce p26 phosphorylation. Whereas phosphorylated p26 was detected in the TNF-sensitive breast cancer cell line CRL1500, other TNF-responsive tumor cell lines investigated lacked enhanced phosphorylation of p26 in response to TNF, indicating that the 26-kDa phosphoprotein (pp26) may be a cell type-specific second messenger molecule involved in TNF signal transduction in some, but not all, target cells. p26 is also phosphorylated in a subclone of U937 (U937.C27) that responds to TNF-alpha with differentiation, yet is resistant to TNF-alpha-mediated growth inhibition. In contrast, p26 is not phosphorylated in another U937 derivative (U937.G3) that is resistant to both TNF-alpha-induced growth arrest and differentiation, suggesting that pp26 may play a role in the TNF signaling pathway linked to differentiation processes rather than to growth control.
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PMID:Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein. 253 51

Exposure of plasma membranes isolated from high density resting murine B cells to recombinant IL-4 in the presence of gamma-[32P]-ATP promoted phosphorylation of a protein of Mr = 42,000. The 42 Kd protein kinase substrate could be detected in membranes prepared from low density B cells following a 24 h culture with lipopolysaccharide, but not in membranes prepared from B cells exposed to LPS for 48 h. Treatment of the cells with LPS resulted in the appearance of a number of new membrane-associated phosphoproteins. Treatment with the cytokine also resulted in the disappearance of a protein kinase substrate of Mr = 30,000 from phosphoprotein profiles of membranes prepared from cells exposed to LPS for 24 h. The 42 Kd structure appears to be a protein kinase substrate rather than possessing intrinsic phosphotransferase activity as judged from experiments employing 8-azido-gamma-[32P]-ATP as a photoaffinity label. No 42 Kd species was detectable using this reagent. Experiments employing identical protocols failed to reveal any enhanced or diminished phosphorylation of membrane-associated proteins in human peripheral blood B cells or in human B lymphoma cell lines.
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PMID:The effect of recombinant interleukin 4 upon protein kinase activities associated with murine and human B lymphocyte plasma membranes. 264 82

In heart muscle, the cytokine-inducible isoform of nitric oxide synthase (NOS2) is expressed in both cardiac myocytes and microvascular endothelial cells (CMEC). mRNA levels for both NOS2 and for osteopontin, a multifunctional extracellular matrix phosphoprotein containing and RGD integrin binding domain, are increased in cardiac muscle following intraperitoneal injection of adult rats with lipopolysaccharide. In vitro, interleukin-1 beta and interferon-gamma increased osteopontin mRNA levels in CMEC as well as NOS2 expression in both CMEC and cardiac myocytes. However, osteopontin mRNA levels in heart muscle in vivo, and in cardiac myocytes and CMEC in vitro, also are increased 10-30-fold by the synthetic glucocorticoid dexamethasone, an agent that suppresses cytokine induction of NOS2 in both cell types. The hexapeptide GRGDSP, which interrupts binding of RGD-containing proteins to cell surface integrins, increased NOS2 mRNA, while a synthetic osteopontin peptide analogue decreased NOS2 mRNA and protein levels in both cytokine-pretreated cardiac myocytes and CMEC cultures. Also, transfection with a full-length antisense-osteopontin cDNA in cytokine-pretreated CMEC decreased endogenous osteopontin mRNA and increased NOS2 mRNA levels. These results suggest that osteopontin could regulate the location and extent of NOS2 induction in the heart. Increased expression of osteopontin also may be one mechanism by which glucocorticoids suppress NOS2 activity in cardiac myocytes and microvascular endothelial cells.
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PMID:Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. 749 54

We report that osteopontin (OPN), a secreted, Arg-Gly-Asp-containing phosphoprotein expressed at high levels in the kidney, suppresses nitric oxide (NO) synthesis induced by the inflammatory mediators gamma-interferon and lipopolysaccharide in primary mouse kidney proximal tubule epithelial cells. Northern blot and immunofluorescence analyses of inducible nitric oxide synthase (iNOS) expression revealed that the inflammatory mediators increased iNOS mRNA and protein levels. Recombinant human OPN (purified from both mammalian cells and from Escherichia coli) inhibited this response by a process that was blocked by anti-OPN antiserum and by the peptide GRGDS, but not GRGES. The data suggest that inhibition of NO synthesis by OPN in these kidney cells is mediated by an integrin, possibly the alpha v beta 3 integrin, which is known to be an OPN receptor. NO is believed to control blood flow through the glomerulus, regulating salt and water balance, and to be important as a defense against tumor cells and infecting microorganisms. The ability of OPN to inhibit the induction of iNOS suggests that OPN may be an important regulator of the NO signaling pathway and NO-mediated cytotoxic processes.
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PMID:Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. 750 62

The signal transduction events that follow the binding of lipopolysaccharide (LPS) to the macrophage cell surface are not well defined. In the current studies LPS was found to induce alterations in phosphorylation of monocyte proteins on tyrosine. Herbimycin A and genistein, inhibitors of tyrosine kinases, markedly attenuated LPS-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) protein and mRNA production. Reciprocally, the tyrosine phosphatase inhibitor sodium orthovanadate enhanced LPS-induced production of TNF-alpha. LPS induced a concentration-dependent increase in tyrosine phosphorylation of several proteins, which paralleled and preceded the onset of LPS-induced TNF-alpha production. LPS stimulation had different but reproducible effects on three members of the src family of tyrosine kinases. Both Hck and Lyn kinase activity increased before the onset of TNF-alpha production, consistent with their participation in the observed LPS-induced tyrosine phosphoprotein accumulation. In contrast, Yes kinase activity was not affected. These observations were made at concentrations of LPS that required serum rich in LPS-binding protein and the monocyte surface antigen CD14 for TNF-alpha production. These data indicate that tyrosine kinases and phosphatases are involved in the signal transduction cascade by which LPS induces production of TNF-alpha and IL-6 by human monocytes, and suggest that Lyn and Hck are candidate participants in this process.
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PMID:Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction. 751 9

Incubation of the mouse B-lymphoma cell line 70Z/3 with bacterial lipopolysaccharide (LPS) results in the secretion of immunoglobulin M (IgM) to the cell surface. We now demonstrate that LPS rapidly induces the tyrosine phosphorylation of a 41 kDa protein in 70Z/3 cells transfected with CD14, a glycosyl phosphatidylinositol-anchored membrane receptor for complexes of LPS and LPS binding protein. There was no indication of LPS-mediated tyrosine phosphorylation in untransfected 70Z/3 cells, which do not express CD14. The 41 kDa tyrosine phosphoprotein was specifically induced by LPS, since it was not observed after incubation with another activator of IgM expression, interferon-gamma. Induction of this 41 kDa phosphoprotein was not observed when the transfected cells were treated with LPS in the absence of serum. Phosphorylation was also blocked by preincubation of the cells with an antibody to CD14. Furthermore, lipid A from Rhodobacter sphaeroides inhibited LPS-mediated tyrosine phosphorylation and surface IgM expression. Expression of CD14 in the LPS-unresponsive mutant 70Z/3 cell line 1.3E2 did not result in the secretion of IgM, although tyrosine phosphorylation was increased after incubation with LPS, suggesting that the mutation in these cells is downstream of the membrane LPS receptor.
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PMID:CD14-dependent induction of protein tyrosine phosphorylation by lipopolysaccharide in murine B-lymphoma cells. 752 Feb 84

Tenidap is a novel antirheumatic drug that combines cyclooxygenase inhibition with cytokine modulating qualities. We demonstrate here that tenidap inhibits the zymosan-induced expression of both interleukin 1 and tumor necrosis factor alpha in macrophages, at the mRNA and protein levels. The concentration-dependence of the tenidap-induced inhibition of the expression of mRNA for these proinflammatory cytokines agrees with that of its inhibitory effects on zymosan-induced arachidonate mobilization and changes in phosphoprotein pattern. The effects of tenidap on the lipopolysaccharide-induced expression of these cytokines are more complex. Tenidap inhibits the induction of interleukin 1 by lipopolysaccharide or bacteria, but less potently than the interleukin 1-response induced by zymosan. In contrast, the drug markedly potentiates the lipopolysaccharide-induced expression of tumor necrosis factor alpha at both the mRNA and protein levels. The latter effect is demonstrated to be due to cyclooxygenase inhibition and is reversed by prostaglandin E2.
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PMID:Differential effects of tenidap on the zymosan- and lipopolysaccharide-induced expression of mRNA for proinflammatory cytokines in macrophages. 867 6


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