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)

The human beta 2 interferon (IFN-beta 2) gene, a gene that also codes for B cell differentiation factor 2 (BSF-2), plasmacytoma/hybridoma growth factor (HGF), and hepatocyte-stimulating factor (HSF), is expressed in a variety of lymphoid and nonlymphoid tissues. Endotoxin, or bacterial lipopolysaccharide (LPS) preparations derived from the outer membrane of Escherichia coli or Salmonella typhimurium rapidly elevate IFN-beta 2 mRNA level in human skin fibroblasts (FS-4 strain). E. coli-derived LPS enhances IFN-beta 2 mRNA expression in FS-4 fibroblasts at a concentration as low as 0.3 ng/ml; this response is near-maximal in the range of 0.1-1 microgram/ml LPS. The increase in IFN-beta 2 mRNA level caused by LPS in FS-4 cells is detected within 30 min after addition of LPS, is sustained for at least 20 h thereafter, appears to involve the protein kinase C signal transduction pathway, does not require new protein synthesis, and is inhibited by dexamethasone in a dose-dependent fashion (in the range 10(-6)-10(-8) M). Cultures of LPS-treated FS-4 cells exhibit an antiviral state against vesicular stomatitis virus, which can be prevented by anti-IFN-beta antiserum. Medium obtained from LPS-treated FS-4 cell cultures enhances the number of immunoglobulin-secreting cells in cultures of human B-lymphoblastoid (CESS) cells. Thus, LPS may trigger a number of host defense mechanisms in the course of infection due to Gram-negative bacteria by enhancing IFN-beta 2 production by the ubiquitous fibroblast.
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PMID:Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion of beta 2 interferon by human fibroblasts. 282 51

The cyclic undecapeptide cyclosporine A (CsA) is a potent immunosuppressive agent that inhibits the initial activation of T lymphocytes. This agent appears to be most effective in blocking the action of mitogens such as concanavalin A and the calcium ionophore A23187, which cause an influx of Ca2+, but not those that may act by alternate mechanisms. These observations suggest that CsA may block a Ca2+-dependent step in T cell activation. We have shown that stimulation of the T3-T cell receptor complex-associated Ca2+ transporter activates the Na+/H+ antiport (Rosoff, P. M., and L. C. Cantley, 1985, J. Biol. Chem., 260: 14053-14059). The tumor-promoting phorbol esters, which are co-mitogenic for T cells, activate the exchanger by a separate pathway which is mediated by protein kinase C. Both the rise in intracellular Ca2+ and intracellular pH may be necessary for the successful triggering of cellular activation. In this report we show that CsA blocks the T3-T cell receptor-stimulated, Ca2+ influx-dependent activation of Na+/H+ exchange, but not the phorbol ester-mediated pathway in a transformed human T cell line. CsA inhibited mitogen-stimulation of interleukin-2 production in a separate cell line. CsA also inhibited vasopressin stimulation of the antiporter in normal rat kidney fibroblasts, but had no effect on serum or 12-O-tetradecanoyl phorbol 13-acetate stimulation. CsA did not affect serum or vasopressin or serum stimulation of normal rat kidney cell proliferation. CsA also had no effect on lipopolysaccharide or phorbol ester stimulation of Na+/H+ exchange activity or induction of differentiation in 70Z/3 pre-B lymphocytes in which these events are initiated by the protein kinase C pathway. These data suggest that mechanisms of activation of Na+/H+ exchange that involve an elevation in cytosolic Ca2+ are blocked by CsA but that C kinase-mediated regulation is unaffected. The importance of the Na+/H+ antiport in the regulation of growth and differentiation of T cells is discussed.
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PMID:Cyclosporine A inhibits Ca2+-dependent stimulation of the Na+/H+ antiport in human T cells. 301 82

Platelet-activating factor (PAF) is a phospholipid mediator of inflammation that is synthesized by several human cell types including polymorphonuclear leukocytes (PMN). We examined the synthesis and release of PAF by stimulated human PMN under several conditions, assayed by the incorporation of [3H]acetate into PAF and by bioassay. PAF synthesis was induced by calcium ionophore A23187 (IoA), opsonized zymosan (OpsZ), and N-formyl-methionyl-leucyl-phenylalanine (FMLP) with the relative order of potency IoA much greater than OpsZ greater than FMLP. A variety of other agonists, including phorbol myristate acetate, an activator of protein kinase C and of PMN functional responses, did not stimulate PAF synthesis. PAF synthesis by PMN in response to IoA, OpsZ, and FMLP was concentration- and time-dependent but release of the phospholipid was not: little PAF (1 to 10%) was released from PMN in suspension regardless of the total amount produced, the agonist, its concentration, the time of incubation, or the concentration of extracellular albumin. This was also the case with functionally altered neutrophils that had been "primed" with cytochalasin B or lipopolysaccharide or that had adhered to surfaces. PAF synthesis was tightly coupled with leukotriene B4 production by adherent PMN as well as by neutrophils in suspension, supporting the hypothesis that the two lipid autacoids may be derived from a common precursor. However, PAF synthesis could be dissociated from aggregation and surface adhesion, indicating that it is not absolutely required for these responses of activated PMN. The total amount of PAF that accumulated, but not the percentage that was released, was altered in adherent PMN compared to cells in suspension. These experiments demonstrate that PAF production and its subsequent processing by human neutrophils are highly regulated events. PAF synthesis is associated with PMN activation, but it is not a requisite for early adhesive responses of neutrophils. Because little of the PAF produced by stimulated PMN is released from the cells, it appears that PAF has an intracellular role in PMN function and/or that it may have novel intercellular effects that do not require release into the fluid phase.
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PMID:Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism. 303 16

The biochemical events leading to enhanced membrane expression of HLA-DR and CR3 by human peripheral blood monocytes (MO) following exposure to bacterial lipopolysaccharide (LPS) were examined. In a previous study we demonstrated that an increase in intracellular calcium was necessary, but not sufficient, for MO to increase membrane expression of both antigens within 1 hr of addition of LPS. The present study was initiated to examine the other biochemical requirements which lead to the MO response to LPS. Enhanced expression of both antigens following addition of LPS was dependent on microfilament function, but independent of microtubule function and of protein synthesis. Inhibition of formation of cyclooxygenase or lipoxygenase metabolites of arachidonic acid had no effect on HLA-DR or CR3 modulation by LPS. A role for phosphatidylinositol metabolism was suggested by the inhibition of the MO response to LPS by dibutyryl cAMP and theophylline and by the enhanced expression of both antigens following addition of phorbol diesters. However, H-7, a putative inhibitor of protein kinase C, did not alter the MO response to LPS or phorbol diesters. These results suggest that LPS enhances expression of HLA-DR and CR3 by inducing redistribution of these antigens from an intracellular pool. The data also support a role for the generation of hydrolysis products of phosphatidylinositol, leading to calcium redistribution and activation of protein kinase C or other kinases, in the MO response to LPS.
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PMID:Biochemical basis of HLA-DR and CR3 modulation on human peripheral blood monocytes by lipopolysaccharide. 303 40

Phagocytic cells can be primed for enhanced stimulated release of superoxide anion (O2-) by exposure to a variety of biologic agents, including gamma-interferon and lipopolysaccharide. We examined the role of calcium ion in this priming, using the calcium ionophore ionomycin. Preincubation with ionomycin, 1 to 10 nM, primed human neutrophils to release up to 7-fold more O2- during stimulation with 1 microM formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). With 160 nM phorbol myristate acetate as stimulus, ionomycin caused a doubling of O2- production in mouse peritoneal macrophages. Incubation of phagocytes with ionomycin at priming concentrations did not directly stimulate O2- release. Priming of neutrophils occurred in 1-2 min and was associated with a marked reduction in the lag time for O2- release after f-Met-Leu-Phe stimulation and with an increase in the rate of O2- production. Kinetic analysis of NADPH-dependent O2(-)-producing activity in sonicates of resting human neutrophils incubated with sodium dodecyl sulfate suggested that modification of the enzyme responsible for the respiratory burst was not responsible for priming. Priming of neutrophils with ionomycin had no apparent effect on either the activity or subcellular distribution of protein kinase C. The effect of ionomycin on the cytosolic free calcium concentration ([Ca2+]c) was assessed in neutrophils using the calcium-sensitive fluorescent dye fura-2. Ionomycin at priming concentrations caused an approximate doubling of the base-line [Ca2+]c. When neutrophils were exposed to various concentrations of ionomycin, a parallel rise in [Ca2+]c and priming was observed. A rise in [Ca2+]c of approximately 0.8 microM caused half-maximal priming. These results suggest that an increase in [Ca2+]c is not sufficient to initiate release of O2-, but they support the concept that Ca2+ can serve as a second messenger in this event.
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PMID:Priming of neutrophils and macrophages for enhanced release of superoxide anion by the calcium ionophore ionomycin. Implications for regulation of the respiratory burst. 304 Jul 59

Lipid A is the toxic principle of lipopolysaccharide of gram-negative bacteria, which causes a spectrum of changes in blood cells and vascular cells. We now report that human platelets are directly stimulated by endotoxic lipid A that activates protein kinase C. Rapid phosphorylation of a human platelet protein of Mr 47,000, a marker of protein kinase C activation, accompanies secretion of [14C]serotonin and aggregation triggered by endotoxic lipid A. These events are time and concentration dependent, with phosphorylation reaching maximum in 2 min and the concentration of lipid A causing a 50% effect (EC50) between 12 and 15 microM. Phospholipase C activation in lipid A-stimulated platelets was not observed as judged by a lack of generation of [3H]diacylglycerol in [3H]arachidonic acid-labeled platelets and a lack of generation of [32P]-phosphatidic acid in 32PO4-labeled platelets. Lipid A did not induce formation of TXA2 as measured by radioimmunoassay for TXB2. The stimulation of human platelets and activation of protein kinase C by endotoxic lipid A was blocked by lipid X, a structural precursor of lipid A. Lipid X also blocked the stimulation of human platelets by phorbol 12-myristate 13-acetate, suggesting that lipid A, lipid X and phorbol ester share reactive site(s) on the human platelet membrane. Although lipid X inhibited thrombin-induced phosphorylation of P47 it did not suppress secretion of [14C]serotonin, indicating the role of protein kinase C-independent pathways in platelet stimulation by thrombin. The inhibitory effect of lipid X did not involve generation of cyclic AMP in human platelet membrane preparations. These results indicate that human platelets are stimulated by endotoxic lipid A, a naturally occurring biologic modifier of protein kinase C. Due to the widespread presence of this enzyme in blood cells, vascular cells, and neurons, its modulation by lipid A may represent a significant mechanism underlying hematologic and circulatory derangements observed in endotoxic shock in humans.
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PMID:Modulation of human platelet protein kinase C by endotoxic lipid A. 304 71

Both lipopolysaccharide (LPS) and phorbol-12,13-dibutyrate (PDBu), a protein kinase C-activating phorbol ester, induced interleukin-1 (IL-1) production in mouse peritoneal macrophages. Prolonged treatment of the cells with PDBu led to the down-regulation and complete disappearance of protein kinase C. In these cells, PDBu did not increase IL-1 production, but LPS still stimulated IL-1 production although the maximum level was slightly reduced. These results suggest that protein kinase C and another unknown signal pathway are involved in LPS-induced IL-1 production.
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PMID:Possible involvement of protein kinase C in interleukin-1 production by mouse peritoneal macrophages. 308 9

These studies were designed to test the hypothesis that changes in intracellular Ca2+ levels and activation of the calcium ion- and phospholipid-dependent protein kinase C were required for the induction of macrophage tumoricidal activity by interferon-gamma (IFN-gamma). Phenothiazines and R24571, known antagonists of calcium-binding proteins and therefore nonspecific inhibitors of protein kinase C, blocked in a dose-dependent manner the induction of macrophage cytocidal activity by either natural or recombinant IFN-gamma. Macrophages depleted of intracellular Ca2+ by chelation with Quin 2, were also unresponsive to IFN-gamma. These treatments effected neither the binding of IFN-gamma to its cell surface receptor nor the normal intracellular processing of IFN-gamma. Activators of protein kinase C (such as phorbol esters) and Ca2+ ionophores when added alone did not effect the activation state of the macrophage population. However, macrophages exposed to both drugs in combination were elevated into the primed activation state such that in the presence of a second signal (lipopolysaccharide or heat killed Listeria monocytogenes), the cells were triggered to express full levels of tumoricidal activity. The capacity of phorbol esters to induce cellular activation correlated with their ability to bind and to activate protein kinase C. No synergistic effect was observed between IFN-gamma and protein kinase C activators and/or Ca2+ ionophores, indicating that the drugs could only prime and could not trigger macrophages for tumor cell killing. These results thus support the concept that protein kinase C activation and mobilization of intracellular Ca2+ are essential steps in the pathway of IFN-gamma-dependent induction of non-specific tumoricidal activity in macrophages.
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PMID:Role of protein kinase C and intracellular calcium mobilization in the induction of macrophage tumoricidal activity by interferon-gamma. 309 74

Addition of the protein kinase C activators phorbol-12-myristate-13-acetate or 1-oleoyl-2-acetylglycerol, or endotoxin (lipopolysaccharide) or zymosan, to RAW264.7 murine macrophages markedly stimulated prostaglandin E2 synthesis. The protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) blocked prostaglandin E2 synthesis in response to all these agonists. The present results suggest that activation of protein kinase C is a step in the stimulation of arachidonic acid metabolism by agonists in macrophages.
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PMID:Protein kinase C mediates endotoxin and zymosan-induced prostaglandin synthesis. 312 56

Splenic B lymphocytes were stimulated with lipopolysaccharide alone or in combination with phorbol-12,13-dibutyrate, a protein kinase C-activating phorbol ester. The effect of the treatment was analysed at the single cell level with in situ RNA/RNA hybridization. Hybridization with a kappa light chain probe revealed that the whole population had shifted towards a low, but significant, expression of immunoglobulin mRNA. Analysis at the population level was performed by DNA/RNA and RNA/RNA hybridization experiments. It was found that the steady-state levels of mRNA for kappa light chain, IgM heavy chain and J chain were reduced by phorbol ester treatment, while the steady-state level of mRNA for IgD heavy chain was increased. Steady-state levels of mRNA for Ia antigen and alpha-actin were marginally affected.
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PMID:Effects of phorbol esters on B-cell gene expression. 314 52


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