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)

Pulp homogenates were incubated with [14C]-arachidonic acid and the metabolites separated by thin-layer chromatography. The main products of normal pulp were 6-keto-prostaglandin (PG) F1 alpha and 12-hydroxy-eicosatetraenoic acid (12-HETE), further identified by high performance-liquid chromatography. Thromboxane (TX) B2, and PGD2, E2 and F2 alpha were also detected at less than 30 per cent of 6-keto-PGF1 alpha. When the pulp was inflamed by applying bacterial lipopolysaccharide, production of all these metabolites increased; in particular, PGE2 was increased 9.3-fold compared with normal, and 6-keto-PGF1 alpha and HETE 3.8- and 2.0-fold, respectively. An unidentified product, slightly more polar than 12-HETE, was also markedly produced by the inflamed pulp. Thus arachidonic-acid metabolites including lipoxygenase products may be involved in the development of pulpal inflammation.
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PMID:Arachidonic-acid metabolism in normal and experimentally-inflamed rat dental pulp. 312 66

Metabolites of arachidonic acid are potent modulators of many biological events, and their release from macrophages appears to play an important role in immune and inflammatory processes. In addition, metabolites of the cyclooxygenase or lipoxygenase pathway exhibit distinct biological effects. We used a method to determine if human alveolar macrophages (HAM) could be selectively activated to release products of cyclooxygenase or lipoxygenase pathway of arachidonic acid. HAM obtained by bronchoalveolar lavage from individuals were [3H]arachidonic acid labeled and then stimulated with lipopolysaccharide (LPS) or Ca ionophore A23187. Essentially no arachidonate metabolites were released by unstimulated cells. LPS caused dose- and time-dependent release of arachidonate and only cyclooxygenase products; no lipoxygenase products were detected, even in presence of cyclooxygenase inhibition. Metabolites released in response to LPS included thromboxane B2, prostaglandins D2, F2a, E2, and hydroxyheptadecatrienoic acid. A23187 caused a rapid release of arachidonate and 5-lipoxygenase products, leukotriene B4 and 5-hydroxyeicosatetraenoic acid; no cyclooxygenase inhibition. This demonstrates that HAM are specifically activated to release metabolites derived from cyclooxygenase or lipoxygenase pathway of arachidonic acid. Additionally, shunting down an alternate pathway is not induced by use of inhibitors of either pathway. This suggests alveolar macrophages may enhance or suppress various inflammatory or immune processes in lung, in part, by selective release of various derivatives of arachidonic acid.
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PMID:Human alveolar macrophage arachidonic acid metabolism. 313 45

The objective of these studies was to investigate mechanisms of regulation of interleukin 1 (IL-1) production by human monocytes. IL-1 production was measured by augmentation of phytohemagglutinin-induced proliferation of murine thymocytes. Adherent human monocytes incubated in medium for one day exhibited a marked decrease in lipopolysaccharide (LPS)-induced IL-1 production over a second day. Cells pre-incubated in 100 U/ml gamma interferon (gamma-IFN) for 24 h displayed a partial to complete maintenance of LPS-induced IL-1 production. Studies with inhibitors of cyclo-oxygenase or lipoxygenase indicated that prostaglandins or leukotrienes were not responsible for the alterations in IL-1 production observed with cultured cells or for the effects of gamma-IFN. Monocytes were pre-incubated in cycloheximide for 24 h and the drug was washed out. These cells exhibited an enhancement in IL-1 production over a second 24 h culture in the presence of 2 ng/ml LPS. Furthermore, the partial maintenance of LPS-induced IL-1 production seen after cells were pre-incubated in gamma-IFN was markedly increased by the inclusion of 0.25 microgram/ml cycloheximide during the 24 h pre-incubation. These results indicate that IL-1 production may be inhibited by newly-synthesized proteins during maturation in vitro or differentiation of monocytes into macrophages. Pre-incubation in gamma-IFN and cycloheximide leads to separate but synergistic effects on the maintenance of LPS-induced IL-1 production in cultured monocytes.
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PMID:Regulation of interleukin 1 production in human monocytes. I. Effects of gamma-interferon and cycloheximide. 314 77

Nocardia rubra cell wall skeleton (N-CWS) was shown to augment interleukin 1 (IL-1) production from peritoneal resident and exudate macrophages in C3H/HeN mice. The mol. wt of the N-CWS-induced IL-1 product was about 17,000 daltons, which is a similar weight to that obtained by lipopolysaccharide stimulation. The stimulation of IL-1 production by N-CWS was seen as early as 8 h after the start of incubation and peak production was observed at 48 h. Profound effects were seen with 10 micrograms/ml or more of N-CWS. Experiments on the regulation of the N-CWS-augmented IL-1 production showed that prostaglandin E2 inhibited the augmentation, and indomethacin (cyclo-oxygenase inhibitor) further augmented it. Leukotriene B4 and AA861 (lipoxygenase inhibitor) had no effect. Our findings suggest that the previously reported adjuvant effect of N-CWS may, in part, be mediated via its ability to stimulate IL-1 production; and that such a stimulation may be blocked by prostaglandins.
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PMID:Effect of Nocardia rubra cell wall skeleton on interleukin 1 production from mouse peritoneal macrophages. 326 37

We have investigated the role of arachidonic acid metabolites in the regulation of interleukin-1 production by murine peritoneal macrophages. Indomethacin a potent inhibitor of prostaglandin synthesis caused a dose-dependent augmentation of lipopolysaccharide induced interleukin production (up to 7-fold at 5 microM). In contrast, lipoxygenase inhibitors, nordihydroguarietic acid and nafazatrom had no effect at doses that did not significantly decrease prostaglandin synthesis. Added to lipopolysaccharide stimulated cultures, PGE2 was also augmented by indomethacin but unlike lipopolysaccharide treated cultures was suppressed by nordihydroguarietic acid. These data suggest that arachidonate metabolites may be potent autoregulators of macrophage interleukin-1 production.
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PMID:Arachidonic acid metabolites regulate interleukin-1 production. 392 70

In the previous paper we have demonstrated that progesterone-treated lymphocytes of healthy pregnant women produce a 34,000 MW protein that inhibits cytotoxic activity and prostaglandin F2 alpha synthesis. Since recently it has been shown that certain leukotrienes have a stimulatory effect on natural killer activity, in this study an attempt was made to determine whether there is a relationship between cytotoxicity and PGF2 alpha synthesis or if alterations in the values of these parameters are independent. Arachidonic acid increased cytotoxic activity of healthy pregnant women's peripheral blood mononuclear cells (PBMC) in a concentration-dependent manner. Exogenous arachidonic acid was able to counteract the blocking effect of the above-mentioned protein produced by progesterone-treated lymphocytes. To determine whether the products of the cyclooxygenase or the lipoxygenase pathway of arachidonic acid metabolism are responsible for increased cytotoxicity, both enzyme systems were blocked separately. Both indomethacin and the lipoxygenase inhibitor BW 755C reduced cytotoxicity in a dose-dependent fashion. However, the lipoxygenase inhibitor prevented prostaglandin synthesis to the same extent, or even more than indomethacin, in all concentrations used; so, its blocking effect cannot be considered as supportive evidence for the role of leukotrienes in cytotoxicity. On the other hand, lipopolysaccharide, with a selective stimulatory effect on prostaglandin synthesis, increased cytotoxicity. Lipopolysaccharide had no effect on progesterone-pretreated PBMC. The above data allow the assumption that besides leukotrienes, cyclooxygenase products may also increase cytotoxicity.
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PMID:The mechanism of the inhibitory effect of progesterone on lymphocyte cytotoxicity: II. Relationship between cytotoxicity and the cyclooxygenase pathway of arachidonic acid metabolism. 393 86

The lethal action of endotoxin was studied in mice sensitized against the lipopolysaccharide by D-galactosamine. Protection was obtained by FPL 55712, a selective antagonist of sulfidopeptide leukotrienes, by diethylcarbamazine, an inhibitor of leukotriene biosynthesis, by BW 755C, a dual lipoxygenase and cyclooxygenase inhibitor, and by dexamethasone, which inhibits arachidonate release. Indomethacin incompletely antagonized endotoxin lethality; indoprofen did not protect at all. Leukotriene generation induced by endotoxin in vivo could be demonstrated in rats by employing a radioimmunoassay on bile extracts since intravascular sulfidopeptide leukotrienes were rapidly eliminated into bile. Additionally, however, endotoxin affected the hepatobiliary elimination of sulfidopeptide leukotrienes. From intravenously injected tracer [3H]leukotriene D4, 67% appeared only partially metabolized in bile within 30 min in control rats. Endotoxin and lipid A reduced the biliary [3H]leukotriene D4 secretion by up to 80% while enhancing the hepatic [3H]leukotriene D4 content up to twofold. This inhibition of hepatobiliary elimination was stronger than endotoxin-induced reductions of bile flow or of biliary [14C]taurocholate secretion. Endotoxin, as an activator of the arachidonate cascade, thus potentiates its action in vivo by interfering with the rapid hepatobiliary clearance of sulfidopeptide leukotrienes in addition to stimulating leukotriene and prostanoid formation.
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PMID:Role of peptide leukotrienes and their hepatobiliary elimination in endotoxin action. 609 38

The synthesis and secretion of prostaglandins and leukotrienes by mouse peritoneal macrophages is under several regulatory controls. Arachidonic acid must first be released from phospholipid stores by the action of phospholipases. Macrophages have the capacity to deacylate arachidonic acid directly from the SN2 position of phospholipids via the action of a phospholipase A2. In addition, these cells contain a phospholipase C capable of removing inositol-phosphate from phosphatidylinositol generating diacylglycerol. Another enzyme, diacylglycerol lipase is present to then generate arachidonic acid. The free arachidonic acid then enters the cyclooxygenase pathway to generate prostaglandins, the lipoxygenase pathway to generate leukotrienes or both pathways. The nature of the inflammatory stimulus added to these cells determines which of the above pathways become operative. Zymosan and the Ca++ ionophore, A23187 stimulate the synthesis of both prostaglandins and leukotrienes whereas phorbol myristate acetate and lipopolysaccharide induce only the synthesis of prostaglandins. In addition, the synthesis of these two products by macrophages can be regulated by certain antiinflammatory compounds. Indomethacin, aspirin, ibuprofen and benoxaprofen are only inhibitors of the prostaglandin pathway, whereas BW755C, 5,8,11-ETYA, NDGA and sulindac sulfide (high doses) are inhibitors of the synthesis of both prostaglandins and leukotrienes. Dapsone, an effective drug for leprosy, also inhibits the synthesis of both of these products.
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PMID:Physiological and pharmacological regulation of prostaglandin and leukotriene production by macrophages. 632

Nordihydroguaiaretic acid (4,4'-[2,3-dimethyl tetramethylene]-dipyrpcatechol) (NDGA), a reportedly specific lipoxygenase inhibitor, suppressed the in vitro murine plaque-forming cell (PFC) response to a thymus-dependent (TD) antigen, and the two subclasses of thymus-independent (TI) antigens, TI1 and TI2, at a final concentration of 33 microM. Suppression kinetics were inconsistent with those observed in previous experiments for other lipoxygenase inhibitors, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), in that BHA and BHT exert suppression early in the 5-day PFC culture system, whereas NDGA suppressed through the 96th h of the 120 h culture period. The sulfhydryl-protective agent 2-mercaptoethanol (2ME) protected both the TD and TI responses. Dibutyryl cyclic GMP (dbcGMP) failed to restore NDGA-suppressed TD and TI1 PFC responses but restored the TI2 response when added at 0-, 24-, 48-, 72-, and 96-h at concentrations of 1-2 mM. NDGA inhibited lipopolysaccharide- (LPS-) induced increases in murine splenocyte cyclic GMP (cGMP) levels, and dbcGMP failed to accelerate the onset of the TI2 PFC response appreciably. The results of these and other laboratory studies indicated that NDGA may not be a specific inhibitor of lipoxygenase. Furthermore, the B-cell subset responding to TI2 antigens may be separated from the TD- and TI1-responding subsets because of the ability of dbcGMP to restore NDGA-suppressed TI2 responses but not the TD or TI1 response. The results suggest a fundamental difference in the biochemical pathways of B-cell subsets, and that cGMP metabolism in some cells may be linked to specific protein synthesis.
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PMID:Differential effects of nordihydroguaiaretic acid (NDGA) on B-cell subsets: reversal of NDGA-induced antibody suppression by cyclic GMP is subset specific. 632 41

The serous membranes of the rabbit peritoneal cavity are tissues in which cyclo-oxygenase and lipoxygenase pathways of arachidonate metabolism can be studied simultaneously. After elaboration of the optimum conditions, the metabolism of two concentrations of arachidonic acid (AA) was studied in the presence and absence of endotoxin lipopolysaccharide (LPS) from E. coli O127:B8 (0.1 and 1.0 mg/ml). LPS suppressed the formation of radiolabelled cyclo-oxygenase products (predominantly prostacyclin) at the lower concentration of exogenous AA (0.8 microM), but not at the higher substrate concentration (34.5 microM). The biosynthesis of lipoxygenase metabolites, i.e. monohydroxyeicosatetra-enoic acids (HETEs), was not influenced by LPS. These findings can be explained by an enhanced release of endogenous AA in the prostacyclin forming mesothelial cells in the presence of LPS. Measurements of the endogenous biosynthesis of prostacyclin supported this assumption.
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PMID:Influence of endotoxin on arachidonate metabolism in isolated rabbit peritoneum. 641 18


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