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)

CGP 47969A is a novel piperazine derivative that inhibits the synthesis of inflammatory cytokines, such as interleukin-1 alpha (IL-1), IL-1 beta and tumor necrosis factor alpha (TNF), in human monocytes stimulated with lipopolysaccharide (LPS), zymosan or IL-1 itself. IC50 values are in the range of 0.3-5 mumol/l. CGP 47969A does not inhibit total protein or RNA synthesis indicating selectivity for cytokine inhibition. CGP 47969A exerts its inhibitory effect at a post-transcriptional level, most probably by reducing translational efficiency of IL-beta mRNA, as steady-state levels of IL-1 beta mRNA are not inhibited while the primary translation product, the 31 kD IL-1 beta precursor molecule, is dose-dependently inhibited by CGP 47969A. The compound is devoid of cyclooxygenase and phospholipase A2 inhibitory activity but efficiently inhibits the generation of PGE2 and LTC4 in zymosan-stimulated mouse macrophages with an IC50 of 1.2 and 0.6 mumol/l, respectively. Antagonism of IL-1 and/or TNF is thought to have a beneficial effect on the course of inflammatory diseases. CGP 47969A may therefore represent a mechanistically new approach to the treatment of such diseases.
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PMID:CGP 47969A: a novel inhibitor of the synthesis of inflammatory cytokines. 774 Oct 42

Interleukin-1 (IL-1) and IL-6 are produced by Sertoli cells. As IL-1 stimulates IL-6 production in some tissues, the cascade of events that results in IL-6 secretion by Sertoli cells was studied. The addition of IL-1 alpha to Sertoli cells resulted in a time-dependent increase in IL-6 secretion. Incubation of Sertoli cells with two known stimulators of IL-1 production, lipopolysaccharide (LPS) and residual bodies, resulted in a significant increase in IL-1 release into the medium several hours before IL-6 release. That IL-1 is essential for IL-6 production from Sertoli cells was established by blocking the actions of LPS and residual bodies with an anti-IL-1 alpha antibody. An increase in the release of IL-1 before IL-6 was also observed in medium obtained from staged segments of intact seminiferous tubules; IL-1 reached a maximum level at stage VIII, when mature spermatozoa are released and residual bodies are formed and phagocytosed. The secretion of IL-6 was low during this stage and then increased progressively from stage IX onward, consistent with IL-1 stimulation of IL-6. The pathway of IL-1 alpha-induced release of IL-6 was studied in the presence of agents that influence arachidonic acid release and metabolism. IL-1 alpha was found to stimulate arachidonic acid release by Sertoli cells. Furthermore, a phospholipase A2 inhibitor, aristolochic acid, significantly decreased IL-1-, LPS-, and pyrularia pubera thionin-induced IL-6 secretion from Sertoli cells. Indomethacin, a specific inhibitor of the cyclooxygenase pathway, had no significant effect on basal, but enhanced IL-1- and LPS-stimulated IL-6 production. The involvement of arachidonic acid metabolites produced in the lipoxygenase pathway on the release of IL-6 was investigated indirectly, using nordihydroguaiaretic acid. This inhibitor reduced basal and IL-1 alpha- and LPS-stimulated IL-6 production. Ethacrynic acid, an inhibitor of peptido-leukotriene synthesis, also reduced basal IL-6 levels and blocked IL-1 alpha- as well as LPS-induced IL-6 secretion. It is concluded that IL-1 produced by Sertoli cells in response to LPS or residual bodies induces IL-6 through the lipoxygenase pathway.
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PMID:Residual bodies activate Sertoli cell interleukin-1 alpha (IL-1 alpha) release, which triggers IL-6 production by an autocrine mechanism, through the lipoxygenase pathway. 778 34

Circulating proinflammatory mediators have not been found in studies on typhoid fever, although the patients suffer from a systemic disease with characteristic protracted fever. The 14-kDa group II extracellular phospholipase A2 (PLA2) is induced by interleukin-1 and tumor necrosis factor and may mediate some of the effects of these cytokines. Circulating PLA2 concentrations were measured in 12 typhoid fever patients on various days after admission and after recovery. On admission, mean concentrations of PLA2 were elevated (1444 +/- 1560 ng/mL) and decreased gradually and significantly to day 14 (55 +/- 48 ng/mL). patients with complicated disease had significantly higher PLA2 levels on admission. PLA2 was not produced in a lipopolysaccharide-stimulated whole blood culture, indicating that PLA2 originates from other types of cells. These data indicate that PLA2 may be a mediator of disease in protracted inflammatory diseases such as thyroid fever.
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PMID:Phospholipase A2 is a circulating mediator in typhoid fever. 779 37

Studies were conducted to characterize a human monocyte model where the role of the 85-kDa phospholipase A2 (PLA2) in prostanoid formation could be evaluated. The presence of an immunologically related 85-kDa PLA2 and type II 14-kDa PLA2 was demonstrated in human monocytes and their roles examined in lipopolysaccharide (LPS)-induced monocyte prostaglandin E2 (PGE2) formation. Exposure of human monocytes to LPS over 18 h resulted in the up-regulation of the mitogen-inducible cyclooxygenase-2 and was accompanied by production and release of prostaglandin E2 but not leukotriene C4. This coincided with a 2-fold increase in the 85-kDa PLA2 protein and activity levels. In contrast, there was no effect on the type II 14-kDa-like PLA2 activity measured in the 100,000 x g particulate fraction nor did LPS induce the release of type II 14-kDa PLA2 into the medium. Treatment with cycloheximide over 18 h resulted in a time-dependent decrease in cytosolic 85-kDa PLA2 protein and activity (half-life = 4 h), but there was no change in the particulate type II 14-kDa-like PLA2 activity. Monocytes were therefore exposed to an 85-kDa PLA2 initiation site-directed antisense oligonucleotide which specifically decreased the cytosolic 85-kDa PLA2 protein levels and activity in a concentration-dependent manner. This had no effect on the cyclooxygenase-2 (protein mass or the ability to convert arachidonic acid to PGE2) or the particulate fraction sn-2 acylhydrolytic activity but was associated with a decrease in LPS-induced PGE2 production. Taken together, these data support a role for the cytosolic 85-kDa PLA2 in LPS-induced monocyte PGE2 formation.
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PMID:Suppression of monocyte 85-kDa phospholipase A2 by antisense and effects on endotoxin-induced prostaglandin biosynthesis. 792 10

Macrophage-like P388D1 cells mobilize arachidonic acid (AA) and produce prostaglandin E2 upon stimulation with bacterial lipopolysaccharide and platelet-activating factor. We have now demonstrated that AA mobilization in these cells is composed of two distinct events: a transient phase in which AA accumulates in the cell and a sustained phase in which the fatty acid accumulates in the incubation medium. Both phases are markedly dependent on the presence of Ca2+ in the extracellular medium. Treatment with an antisense oligonucleotide to group II phospholipase A2 inhibits the accumulation of AA in the incubation medium, but has no effect on the accumulation of this fatty acid in the cell. In addition, treatment with antisense oligonucleotide to group II phospholipase A2 has no effect on the uptake or the esterification of AA. Collectively, these results indicate that, in addition to the previously demonstrated role of group II phospholipase A2 in AA mobilization in activated P388D1 cells, another phospholipase A2, distinct from the group II enzyme, is implicated in raising the levels of intracellular AA during the early steps of P388D1 cell activation and in modulating deacylation/reacylation reactions involving AA. The data suggest that each of the different phospholipase A2 enzymes present in P388D1 cells serves a distinct role in cell function.
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PMID:Arachidonic acid mobilization in P388D1 macrophages is controlled by two distinct Ca(2+)-dependent phospholipase A2 enzymes. 797 9

Cultures of mouse peritoneal resident macrophages produced prostaglandin E2 when exposed to extracellular group II phospholipase A2. The response to group II phospholipase A2 was concentration dependent, and prostaglandin E2 production in response to 1 microgram/ml purified group II enzyme was comparable to the maximal response elicited by lipopolysaccharide. Group II phospholipase A2 required millimolar concentrations of extracellular Ca2+ for the induction of prostaglandin E2 production, as well as for phospholipase A2 activity. YM-26734 (4-(3,5-didodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyph eny l) chroman), a selective inhibitor of group II phospholipase A2, inhibited not only the enzyme activity but also the prostaglandin E2 production-inducing activity of group II phospholipase A2 in a concentration-dependent manner. These findings suggest that group II phospholipase A2 released into the extracellular space may induce prostaglandin E2 production through hydrolysis of plasma membrane phospholipids. Taken together with the previous finding that YM-26734 suppressed inflammatory responses in vivo, these results suggest that group II phospholipase A2 may play a role in the excitation and/or progression of inflammatory processes through the production of eicosanoids.
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PMID:Exogenous group II phospholipase A2 induces prostaglandin E2 production in mouse peritoneal macrophages. 801 41

Infection with a virulent strain of Mycobacterium avium, but not with virulent Mycobacterium tuberculosis or avirulent Mycobacterium smegmatis, induced the formation of nitric oxide by human monocyte-derived macrophages. This process was not affected by lipopolysaccharide or cytokines such as interferon-gamma or tumor necrosis factor alpha. M. avium-induced nitric oxide production was significantly decreased by NG-monomethyl-L-arginine, a potent inhibitor of nitric oxide synthase activity, without any significant enhancement of intramacrophagic mycobacterial growth. Infection with all the three mycobacterial species induced a significant activation of phospholipase A2 activity of macrophages as evidenced by the increased release of thromboxane A2. Finally, nitric oxide production by human monocyte-derived macrophages required infection with live M. avium, as neither gamma-irradiated M. avium nor the subcellular fractions of this microorganism (cell wall, cytosol) were able to trigger nitric oxide synthesis.
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PMID:Selective Mycobacterium avium-induced production of nitric oxide by human monocyte-derived macrophages. 802 68

Stimulation of peripheral blood leukocytes with lipopolysaccharide results in the synthesis of inflammatory cytokines including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha and prostaglandin E2 correlating with an increase in phospholipase A2 activity. Mammalian cells contain several phospholipase A2 isoforms including the 14-kDa secretory isoform and the more recently described high-molecular-mass cytosolic isoform. It is commonly believed that during inflammatory responses secretory phospholipase A2 becomes activated. However, we could not detect secretory phospholipase A2 nor its corresponding mRNA after lipopolysaccharide-induced activation. By contrast, we found increased mRNA levels for cytosolic phospholipase A2 following activation of peripheral blood leukocytes when levels were compared to non-stimulated controls. Our results demonstrate that cytosolic phospholipase A2, rather than the secretory isoform may be the mediator of the lipopolysaccharide-induced inflammatory cascade in human peripheral blood leukocytes.
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PMID:Induction of cytosolic phospholipase A2 in human leukocytes by lipopolysaccharide. 805 50

In the P388D1 macrophage-like cell line, phospholipase A2 activity and prostaglandin production are stimulated by platelet-activating factor (PAF) and bacterial lipopolysaccharide (LPS). We have investigated the role of Ins(1,4,5)P3 and Ca2+ in signal transduction of PAF-induced prostaglandin E2 (PGE2) formation in these cells. The role of Ca2+ in the activation mechanism was studied by fluorescence imaging of intracellular Ca2+ in individual adherent cells and by determining the PGE2 production in the same population of cells. This new approach enabled us to correlate directly events on the single-cell level with a physiologically relevant response of the cell population. Priming the cells with LPS was required for PAF to stimulate PGE2 formation, yet LPS affected neither the intracellular free Ca2+ concentration ([Ca2+]i) nor the PAF-induced rise in [Ca2+]i. In addition, basal and PAF-stimulated Ins(1,4,5)P3 levels were not affected by LPS priming. However, the Ca2+ transient, the release of Ins(1,4,5)P3 and the formation of PGE2 induced by PAF were inhibited in cells pretreated with pertussis toxin. Buffering the [Ca2+]i with intracellular BAPTA [bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid] blocked the PAF-stimulated rise in [Ca2+]i and PGE2 formation. Removal of extracellular Ca2+ during PAF stimulation prevented the influx of Ca2+, but did not affect the initial [Ca2+]i transient, nor did it inhibit PGE2 formation. Under the same conditions, ionomycin stimulated an identical [Ca2+]i transient, but, in contrast with PAF stimulation, no PGE2 formation was observed. PGE2 production could be rescued by prompt subsequent addition of PAF, which caused no further [Ca2+]i change on its own. These results show that the transient initial rise in [Ca2+]i, produced either by PAF via the formation of Ins(1,4,5)P3 or directly by ionomycin, is necessary, but not sufficient for the formation of PGE2 in LPS-primed P388D1 cells. Furthermore, we have demonstrated for the first time that PAF triggers a second signal that is not mediated by a change in [Ca2+]i. However, both signals are required to induce PGE2 formation.
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PMID:Intracellular Ca2+, inositol 1,4,5-trisphosphate and additional signalling in the stimulation by platelet-activating factor of prostaglandin E2 formation in P388D1 macrophage-like cells. 814 66

Preincubation of rat splenic lymphocytes with nonspecific mitogens and calcium ionophore A23187 led to the activity of phospholipase A2 which hydrolyzed arachidonoyl phospholipids and to increased cellular levels of free arachidonic acid. The effect of some substances was decreased as follows: A23187 > > lipopolysaccharide > phytohemagglutinin > concanavalin A. Dose-dependent activation of phospholipid hydrolysis and arachidonic acid release were observed within 6-12 hrs after X-ray irradiation of animals in doses of 0.5 and 1.0 Gy. The involvement of phospholipase A2 in deterioration of receptor interactions occurring during transmission of an activation signal in splenic lymphocytes in the early postirradiation period is discussed.
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PMID:[Phospholipase A2 in the biochemical mechanisms of spleen lymphocyte reaction to x-ray irradiation of animals]. 816 Apr 24


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