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)

To investigate the mechanism of lipopolysaccharide (LPS)-induced endothelial response, we measured the permeability to albumin of cultured pulmonary endothelial cell monolayers. PMA and SC-9, used as activators for protein kinase C (PCK), failed to cause an increase in permeability to albumin. H-7, a potent PKC inhibitor, did not prevent the LPS-induced increase in permeability to albumin. In contrast, H-8, which strongly inhibits cyclic nucleotide-dependent protein kinases, and a calmodulin antagonist prevented the LPS-induced increase in permeability to albumin. These results suggest that calmodulin and protein kinases other than PCK are implicated in the mechanism of LPS-induced increase in permeability to albumin.
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PMID:[Effects of inhibitors of intracellular signal transduction on lipopolysaccharide-induced increase in permeability of cultured pulmonary endothelial cell monolayers]. 831 2

Woodchuck (Marmota monax) hepatic cells, which were immortalized by the simian virus 40 large T antigen (SV40 Tag) produced nitric oxide (NO; measured as nitrite) in vitro from L-arginine (L-Arg) after lipopolysaccharide (LPS) treatment. NO synthesis was related to L-Arg and LPS concentration and plateaued at 1.0 mM L-Arg and 1.0 microgram/ml LPS. LPS-stimulated cells nitrosated morpholine to form N-nitrosomorpholine (NMOR) in the presence of L-Arg at pH 7.4. NMOR production increased 7-fold in LPS stimulated cells compared to unstimulated hepatocytes. N-nitrosodimethylamine (NDMA) was detected in the cell culture medium in the presence of LPS and L-Arg but without added dimethylamine. NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthase, inhibited formation of NO and NMOR, indicating that NO and nitrosating agents were formed via the L-Arg-nitric oxide pathway. These data are the first to report NO and N-nitrosamine production by immortalized hepatocytes and confirm earlier work showing that primary hepatocytes form NO in culture. This suggests that hepatic formation of N-nitroso compounds and/or NO could be an etiologic factor in hepatocellular carcinoma. Immortalized woodchuck hepatic cells may be useful as in vitro models to study the L-Arg-nitric oxide pathway and its possible role in liver carcinogenesis.
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PMID:Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes. 839 80

The effects of the immunosuppressant mycophenolate mofetil (MPAM, RS-61443) on cytokine production at the single cell level were assessed using in vitro activated human mononuclear cells. Cytokine production was studied with UV microscopy of fixed and permeabilized cells stained with cytokine specific monoclonal antibodies (mAbs). The cytokines evaluated included interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10 interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), TNF-beta, and granulocyte macrophage-colony stimulating factor (GM-CSF). MPAM exhibited a marked antiproliferative effect without cytotoxicity in all mononuclear cell cultures. Six to 24 hours after stimulation with the superantigen Staphylococcus aureus enterotoxin A (SEA), most cytokine production was unaffected by MPAM at therapeutic concentrations (10(-6) M), with the exception of GM-CSF. In contrast, by 48 h after antigen activation, MPAM significantly inhibited all studied cytokine production (p < 0.05). Cyclosporin A (CsA), used as a control at a concentration of 100 ng/ml, inhibited production of all studied cytokines, at all time points. Monokine production after lipopolysaccharide (LPS) stimulation was unaffected by MPAM. Similarly, the production of most of the cytokines studied after mitogen stimulation with phorbol ester (PMA) plus calcium ionophore (ionomycin) was not affected by MPAM, in comparison to CsA which demonstrated significant inhibition of all cytokines tested under these conditions. However, a late inhibitory effect on IL-3 production was seen by MPAM at 48 h after mitogenic stimulation. Further observations are required to explain the divergent results on cytokine production by MPAM in superantigen-activated and mitogen-activated human mononuclear cells.
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PMID:Effect of mycophenolate mofetil (RS-61443) on cytokine production: inhibition of superantigen-induced cytokines. 840 81

Transgenic mice have been generated with an inducible SV40 t/T antigen construct with the aim of analysing the early changes that take place in the course of liver tumorigenesis. The strictly liver-specific human C-reactive protein (CRP) gene promoter was chosen for the control of the transgene expression because this promoter can be turned on transiently by injection of bacterial lipopolysaccharide. Among 10 independently derived CRP-Tag mouse lines five showed inducible expression of the CRP-Tag transgene in liver. However, only one had a tight control of the transgene with virtually no expression under physiological conditions and high levels of Tag expression after stimulation. Females of this line were used to analyse the progression of liver alterations upon repeated induction of the t/T antigen for different lengths of time. The first signs of transgene-induced liver alterations could be monitored by the activation of the marker enzyme gamma-glutamyltranspeptidase 30 days after the start of the induction program. After 90 days hepatocellular carcinomas were already detectable. Thus, CRP-Tag mice constitute an excellent system to analyse the sequential events that take place during liver carcinogenesis.
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PMID:Inducible formation of liver tumors in transgenic mice. 842 99

Tolerance to endotoxin (lipopolysaccharide, LPS) was shown to be mediated by an inhibition of cytokine production. We have studied the effect of 3-day pretreatment with LPS on production of IL-6 in response to a subsequent challenge with LPS in a mouse glioma. The results indicated that in this model, a complete blockage of IL-6 production is induced by LPS pretreatment. This is associated with a decrease of LPS-induced IL-6 mRNA levels. LPS-induced IL-6 production can be restored by PMA, as it was previously observed in vivo, suggesting that down-regulation of IL-6 response in LPS tolerance occurs at the transcriptional level, probably by down-regulating protein kinase C or some other PMA-activable signaling system. IL-6 production is also down-regulated by 3-day preincubation with IL-6 and, to a lesser extent, with IL-1 or TNF, indicating that IL-6 can down-regulate its own production.
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PMID:Suppression of interleukin-6 production in endotoxin tolerance in a mouse glioma cell line: reversal by phorbol ester. 845 31

We examined whether the generation of tumor necrosis factor (TNF-alpha) after lipopolysaccharide (LPS) challenge contributes to increases in lung vascular permeability and water content. Guinea pig lungs perfused at constant flow with Ringer-albumin solution (0.5 g/100 ml) were challenged for 120 min with LPS (Escherichia coli; final concentration 33 ng/ml; n = 5). Lung effluent samples were assayed for TNF-alpha activity using the modified L-929 fibroblast cytolytic assay. TNF-alpha concentrations increased in a time-dependent manner with a peak value of 100 +/- 20 pg/ml noted 90-120 min after LPS. Human neutrophils [polymorphonuclear leukocytes (PMN; 2 x 10(7)] added to the perfusion solution after endotoxin challenge (n = 5) produced a threefold increase in lung tissue myeloperoxidase (MPO) activity over control values. PMN, added after LPS and activated using phorbol 12-myristate 13-acetate (PMA; 5 x 10(-9) M; n = 6), produced three- to sixfold increases in mean pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Pcap), wet weight-to-dry weight ratio (W/D), and the pulmonary capillary filtration coefficient (Kf,c) over control values (P < 0.05). Activation of PMN with PMA in non-LPS-challenged lungs produced only threefold increases in Ppa and Pcap and did not change W/D and Kf,c. Infusion of an anti-TNF-alpha antibody before the LPS challenge reduced by approximately 50% the increases in Ppa, Pcap, MPO content, Kf,c, and lung wet weight gain (P < 0.05). Therefore, endotoxin-induced TNF-alpha generation in lungs significantly contributes to pulmonary sequestration of PMN. Activation of the sequestered PMN increases pulmonary vascular permeability and tissue water content.
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PMID:TNF-alpha release in endotoxemia contributes to neutrophil-dependent pulmonary edema. 847 94

Tumor Necrosis Factor alpha (TNF alpha) is a cytokine mediator that is produced primarily by activated monocytes/macrophages in response to endotoxin/lipopolysaccharide (LPS) as well as other stimuli. The second messenger systems that regulate the synthesis and release of TNF alpha are not clearly defined. In the present study, the role of protein kinase C (PKC) in the production of TNF alpha was investigated in human peripheral blood monocytes stimulated with either LPS or zymosan. Two broad spectrum protein kinase inhibitors (staurosporine and K252a) and two PKC specific inhibitors (calphostin C and chelerythrine), were used as probes to delineate the involvement of PKC in the production of TNF alpha. The results indicate that inhibition of PKC diminished LPS- or zymosan- induced TNF alpha production in a concentration-dependent manner. The IC50 values for the inhibition of TNF alpha production were 0.2 nM for staurosporine, and 20 nM for K252a, Calphostin C and chelerythrine. Furthermore, long term PMA treatment of these cells (to abrogate PKC-mediated responses) resulted in a significant reduction of stimuli-induced TNF alpha production. LPS and zymosan also induced an increase in membrane associated PKC activity in human monocytes, which could be inhibited by pretreatment of the cells with calphostin C. Finally, western blot analysis with PKC isoform-specific antibodies demonstrates that the alpha and xi are the predominent isoforms expressed in human monocytes. These data strongly suggest that an initial step in TNF alpha production by human monocytes challenged with physiological stimulants, such as LPS and zymosan, involves a PKC-dependent mechanism.
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PMID:Protein kinase C regulates TNF-alpha production by human monocytes. 849 Jan 3

The U937 cell, a human monoblast cell line, has been used as a model to study the function of human monocytes. We investigated the effects of interferon-gamma (IFN-gamma) on superoxide anion (O2-) production, cell surface antigens, and cytokine production of U937 cells. IFN-gamma treatment enhanced O2- production of fMLP or PMA-stimulated U937 cells. IFN-gamma increased the ratio of CD23 and CD11b positive cells. The fluorescence intensity of CD14 and CD25 was enhanced by IFN-gamma treatment. U937 cells produced IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha by lipopolysaccharide (LPS) stimulation. IFN-gamma treatment enhanced TNF-alpha production, but decreased IL-6 production. These results suggest that IFN-gamma differentiates U937 cells to monocyte-like cells and it regulates the production systems of IL-6 and TNF-alpha separately in U937 cells.
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PMID:Effects of interferon-gamma on cell differentiation and cytokine production of a human monoblast cell line, U937. 859 30

The respiratory burst of phagocytes in an important leukocyte function which results in generation of oxygen species that are both microbicidal and potentially damaging to host tissues. We investigated regulation of the respiratory burst of alveolar macrophages in response to lipopolysaccharide (LPS) derived from gram-negative bacteria, serum proteins, and several modulators of signal transduction. When employed as a single stimulus, LPS (E. coli 055:B5, 10 ng/ml-1 microgram/ml) was a weak stimulus for generation of superoxide anion (O2-) as compared to the potent effect of the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA; 500 ng/ml). However, when LPS was combined with fetal bovine serum (FBS; 0.4-1.0% vol/vol, equivalent to 128-320 micrograms protein/ml), O2- generation was enhanced approximately two-fold over LPS alone. A chromatographically-derived bovine serum fraction which contained bovine lipopolysaccharide-binding protein (bLBP; 0.25-1.0 microgram/ml) was an effective substitute for FBS at a much lower protein concentration than whole FBS, and a similar synergistic effect with LPS on O2- generation was observed. Stimulation of macrophages for generation of O2- either with LPS alone or with LPS plus serum/serum fraction was suppressed by the protein tyrosine kinase inhibitor heribimycin A (0.2 ng/ml), and the calcium chelator BAPTA (12 microM), but not by modulators of G-proteins, including pertussis toxin (10 ng/ml) and cholera toxin (5 micrograms/ml protein). Essentially complete inhibition of O2- synthesis by herbimycin A and BAPTA occurred in the presence of LPS and the bLBP-containing serum fraction (1 microgram/ml protein), but only partial inhibition (46.7% and 64.1%, respectively) was observed in the presence of LPS plus FBS (256 micrograms/ml protein). These results indicate that when LPS is used as a sole stimulus it induces modest respiratory burst activity. However, when LPS is combined with appropriate serum components, it stimulates alveolar macrophages to generate larger amounts of O2-. Cellular signaling pathways important in stimulation of macrophages by LPS and serum components are protein tyrosine kinase- and Ca(++)-dependent, but do not relay on G-protein-mediated signaling.
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PMID:Regulation of superoxide anion generation in bovine alveolar macrophages by bacterial lipopolysaccharide, serum proteins, and modulators of signal transduction. 859 31

CD36 is an 88-kD integral membrane protein expressed on platelets, monocytes, macrophages, certain microvascular endothelia, and retinal pigment epithelium. It functions as an adhesive receptor for thrombospondin-1 (TSP-1), collagen, and malaria-infected erythrocytes and as a scavenger receptor for oxidized LDL and photoreceptor outer segments. The CD36-TSP-1 interaction plays a role in cell adhesion and the phagocytosis of apoptotic cells by macrophages. Because of the potential importance of the CD36-TSP-1 interaction in mediating atherogenic and inflammatory processes, we studied their expression in human peripheral blood monocytes exposed to soluble mediators known to regulate inflammation and atherogenesis. RNase protection assays showed 6- to 12-fold increases in CD36 mRNA in response to interleukin-4, monocyte colony-stimulating factor, and phorbol myristate acetate, while lipopolysaccharide and dexamethasone strongly downregulated CD36 mRNA. The downregulation of CD36 mRNA was associated with the disappearance of surface expression of CD36 antigen and loss of TSP-1 surface-binding capacity. Upregulation of CD36 mRNA was associated with a modest increase in surface antigen expression and a larger expansion of an intracellular pool of CD36. As with CD36, monocytes treated with monocyte colony-stimulating factor showed a rapid increase in TSP-1 mRNA expression. Moreover, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA, and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. Interferon gamma, which had no effect on CD36 mRNA, rapidly increased steady-state TSP-1 mRNA. Thus, expression of both CD36 and its ligand TSP-1 is regulated by soluble mediators, although certain mediators induce concordant changes and others discordant changes.
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PMID:Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. 869 41


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