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)

We examined the role of cyclooxygenase (CO)-derived metabolites of arachidonic acid (AA) in the regulation of interleukin 1 (IL 1) production by lipopolysaccharide (LPS)-stimulated murine resident peritoneal macrophages. The use of LPS proved to be an efficacious probe, because it stimulated both IL 1 production and AA metabolism via only the CO pathway. The production of the CO metabolites prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2; measured as its stable metabolite 6-Keto prostaglandin F1 alpha) by LPS-stimulated macrophages was demonstrated by high pressure liquid chromatography and radioimmunoassay. The addition of exogenous PGE2 or PGI2 resulted in a dose-dependent suppression of macrophage IL 1 production. Inhibitors of the CO pathway (indomethacin, piroxicam, and ibuprofen) caused a dose-dependent augmentation in the LPS-induced IL 1 response. This augmentation directly correlated with the efficacy of the compounds as CO inhibitors. Similar results were found when macrophage-derived fibroblast growth factor was assessed. The addition of exogenous IL 1 to macrophage cultures caused an increase in the levels of PGE2, over a narrow dose range (0.05 to 0.6 IL 1 units). These studies provide detailed evidence that AA metabolites synthesized via the CO pathway can modulate the production of growth factors by LPS-stimulated macrophages. In addition, our data support the concept that IL 1, as with classical hormones, can regulate its own production through a self-induced inhibitor, PGE2.
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PMID:Prostaglandins as endogenous mediators of interleukin 1 production. 307 6

C3b or lipopolysaccharide treatment of human peripheral blood monocytes in culture stimulates an early release of thromboxane B2 and a delayed release of prostaglandin E into culture supernatants. Immunoreactive thromboxane B2 release is maximal from 2-8 h, whereas prostaglandin E release is maximal from 16-24 h after stimulation of monocytes in culture. We further examined this process by comparing the time course of labelled prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes which were pulse or continuously labelled with [3H]arachidonic acid and [14C]eicosatrienoic acid. The release of labelled eicosanoids was compared with the release of immunoreactive prostaglandin E and thromboxane B2. The time course of prostaglandin E2 release was virtually identical to the release of prostaglandin E1 in all culture supernatants regardless of labelling conditions. However, release of immunoreactive prostaglandin E paralleled the release of labelled prostaglandin E1 and E2 only for continuously labelled cultures. The release of labelled prostaglandin E1 and E2 from pulse labelled cultures paralleled the release of thromboxane B2 and not immunoreactive prostaglandin. In contrast, labelled and immunoreactive thromboxane B2, quantitated in the same culture supernatants, demonstrated similar release patterns regardless of labelling conditions. These findings indicate that the differential pattern of prostaglandin E and thromboxane B2 release from human monocytes is not related to a time-dependent shift in the release of prostaglandin E1 relative to prostaglandin E2. Because thromboxane B2 and prostaglandin E2 are produced through cyclooxygenase mediated conversion of arachidonic acid, these results further suggest that prostaglandin E2 and thromboxane B2 are independently metabolized in human monocyte populations.
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PMID:Prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes treated with C3b or bacterial lipopolysaccharide. 310 43

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

We investigated the capacity of counterflow-isolated human monocytes to independently synthesize thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) when stimulated with bacterial lipopolysaccharide (LPS). Independent metabolism was confirmed by establishing different specific activities (dpm/ng) of TxB2 and PGE2 released from LPS-treated cells. For metabolites released during the initial 2-hr treatment period, the specific activity of PGE2 was approximately threefold higher than that of TxB2 regardless of labeling with [3H]arachidonic acid (AA) or [14C]AA. Cells that were pulse-labeled for 2 hr with [3H]AA demonstrated a decreasing PGE2 specific activity over 24 hr, whereas the TxB2 specific activity remained unchanged. In contrast, cells continuously exposed to [14C]AA demonstrated an increasing TxB2 specific activity that approached the level of PGE2 by 24 hr. These results suggest the presence of at least 2 cyclooxygenase metabolic compartments in counterflow-isolated monocytes. Although freshly isolated monocytes have been reported to contain variable numbers of adherent platelets, additional experiments demonstrated that counterflow-isolated platelets are not capable of releasing elevated levels of TxB2 or PGE2 when treated with LPS. It is proposed from these findings that at least two subsets of monocytes exist in peripheral blood that can be distinguished on the basis of independent conversion of AA to TxB2 and PGE2.
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PMID:Prostaglandin E2 and thromboxane B2 release from human monocytes treated with bacterial lipopolysaccharide. 314 40

The pyrogenic properties of high purified recombinant human tumor necrosis factor (rHu-TNF) were investigated in rabbits. rHu-TNF produced a clear biphasic fever reaching maximal values at 1 and 5 hr after bolus i.v. injections of 10 and 33 micrograms/kg; the initial febrile response was short-lasting, and not dose-related, but the second one was dose-related and lasted for 10 hr or more. The febrile response to rHu-TNF, unlike lipopolysaccharide, did not decrease after a single or two consecutive doses. A significant reduction in the febrile response, however, was seen after four consecutive doses starting from 7 days after the second dose; the febrile response 3 hr after rHu-TNF was much smaller, but the first peak was hardly smaller. Low anti-rHu-TNF levels were found in serum of rabbits treated repeatedly with rHu-TNF, suggesting that antibody production against rHu-TNF is not responsible for the tolerance formation although it may make some contribution. There was no cross-tolerance between rHu-TNF and lipopolysaccharide. On the other hand, the febrile response to rHu-TNF (33 micrograms/kg i.v.) was inhibited partially or completely blocked by i.v. administration of cyclooxygenase inhibitors or dexamethasone. rHu-TNF produced a marked increase in the cerebrospinal fluid prostaglandin E2 level after bolus i.v. injection. A significant level of rHu-TNF (1.6 and 6.4% of that in serum) was found in cerebrospinal fluid after bolus i.v. injection of 33 and 1000 micrograms/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant human tumor necrosis factor causes long-lasting and prostaglandin-mediated fever, with little tolerance, in rabbits. 316 87

We examined the potential contribution of thromboxanes in human monocyte adherence to plastic. Monocyte adherence to plastic could be augmented by various stimuli including lipopolysaccharide, chemotactic peptide, and supernates of antigen-stimulated lymphocytes. Increments in monocyte adhesiveness were suppressed by inhibition of cyclooxygenase, thromboxane synthetase, or by antiserum to thromboxane B2. Neither prostaglandin E2 or F2 alpha significantly affected baseline or lipopolysaccharide-stimulated monocyte adherence. Additional experiments confirmed incremental production of thromboxane B2 by monocytes after incubation with lipopolysaccharide. Thromboxane B2 itself did not stimulate monocyte adhesiveness. These data demonstrate that monocytes release thromboxane A2 following stimulation and suggest that thromboxane A2 may play a significant role in monocyte-substrate attachment.
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PMID:Mediation of augmented monocyte adhesiveness by thromboxane. 328 22

Human alveolar macrophages obtained from 7 normal volunteers and 7 patients with lung disease were stimulated with endotoxin (lipolysaccharide) to induce interleukin 1/leucocytic pyrogen (IL1/LP) secretion. Using the thymocyte assay we quantitated IL1/LP activity in macrophage supernatants obtained after 24 h. 10 micrograms/ml lipopolysaccharide stimulated alveolar macrophages to secrete significantly more IL1/LP activity than did 1 micrograms/ml. Apart from one patient with sarcoidosis, the presence of indomethacin did not significantly inhibit the quantity of IL1/LP secreted in response to LPS. We also demonstrated that the presence of indomethacin did not affect the response of thymocytes to IL1/LP. We conclude that the secretion of IL1/LP by human alveolar macrophages in response to endotoxin is not significantly reduced by the cyclooxygenase inhibitor indomethacin.
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PMID:Secretion of interleukin 1/leucocytic pyrogen from endotoxin-stimulated human alveolar macrophages is unaffected by indomethacin. 349 Apr 58

The toxicity of various monosaccharide and disaccharide endotoxin precursors has now been studied in sheep. We measured the early pulmonary arterial pressure responses after injections of the monosaccharides lipid X (2,3-diacylglucosamine 1-phosphate) and MAGP (2-monoacylglucosamine 1-phosphate), of the tetraacyl disaccharide diphosphate precursor of lipid A, IV-A (Federation Proc. 43: 1567, 1984), and of Escherichia coli bacterial endotoxin (lipopolysaccharide). We also measured the response of lipid X after prior administration of indomethacin and MAGP. Lipid X, at a total cumulative dose of 40 micrograms/kg, produced an immediate, but transient dose-dependent pulmonary arterial vasoconstrictive response. MAGP, at a total dose of 40 micrograms/kg, had no pulmonary pressure activity but did increase extravascular lung water and produce some histological changes in the lung. Disaccharide precursor IV-A, at a total dose of 40 micrograms/kg, produced an immediate dose-dependent pulmonary arterial vasoconstrictive response that was prolonged for greater than 2 h. E. coli endotoxin caused a delayed (15-min) increase in the pulmonary arterial pressure but one that also persisted for greater than 2 h. Prior administration of indomethacin blocked the pulmonary pressor activity of lipid X, whereas prior administration of MAGP increased both the magnitude and the duration of the pulmonary pressure response of lipid X. We conclude that the initial pulmonary hypertension seen after lipid X injection may involve cyclooxygenase-dependent formation of prostaglandins and that the genesis of this pulmonary pressor activity is at least in part dependent on the ester-linked hydroxymyristoyl moiety at position 3 of the lipid X molecule.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary pressor responses in sheep to chemically defined precursors of E. coli endotoxin. 355 39

Sub-microgram quantities of bacterial lipopolysaccharide (LPS) have been found to substantially reduce the intracellular catalytic activities of three representative lysosomal enzymes (namely, acid phosphatase, hexosaminidase, and beta-glucuronidase) in human monocyte-derived macrophages. This response was not associated with a concurrent increase in enzyme catalytic activity in the culture supernatant, and hence, could not be explained by mobilization of preformed material. By conducting experiments in the presence and absence of indomethacin, a cyclooxygenase inhibitor, the reduction in lysosomal enzyme catalytic activities was shown not to be dependent on the ability of LPS to induce prostaglandin E2 production. The response was not found to be the result of a more generalized LPS-dependent reduction in the ability of the cells to synthesize protein, since the presence of LPS in macrophage cultures did not appreciably affect the amount of [35S]methionine incorporated into total cellular proteins. A kinetic analysis of the effect of LPS on the down-regulation of enzyme catalytic activities indicated that this was an early response of the cells to LPS exposure. An investigation of the effects of blockade of enzyme catabolism (using the lysosomotropic weak-base, methylamine) indicated that the reduction of catalytic enzyme activities in response to LPS was probably due to a decreased rate of production of active product, rather than an enhanced rate of enzyme catabolism. This suggestion was confirmed by experiments in which the synthesis of pro-hexosaminidase (measured by biosynthetic labeling with [35S]methionine and specific immunoprecipitation of labeled pro-hexosaminidase) was found to be reduced by 42% after a 24-h exposure to LPS (although the synthesis of complement component C3 was stimulated by a factor of 4.5). It is suggested that the ability of LPS to regulate the functional expression of protein products contributes to changes in the overall functional status of these cells in response to this bacterial product.
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PMID:Bacterial lipopolysaccharide suppresses the production of catalytically active lysosomal acid hydrolases in human macrophages. 370 Apr 68

The mechanism through which human blood platelets interact with gram-negative bacteria with well-defined structural variations in endotoxic lipopolysaccharide was studied. Secretion of 14C-serotonin and aggregation of platelets separated from plasma proteins were observed on challenge with rough mutant Re595 of Salmonella minnesota possessing a glycolipid outer layer composed of Lipid A and 2-keto-3-deoxyoctonate (KDO) but lacking heptose phosphate in the core and O-polysaccharide in its outer portion. Both 14C-serotonin secretion and platelet aggregation were concentration-dependent, with a half-maximum response at the ratio of one bacterial colony-forming unit (CFU) to two platelets. The aggregation of human platelets induced by mutant Re595 was divalent cation-dependent and required secretion of ADP and fibrinogen from platelet storage granules because it was inhibited by chelators, by the ADP-splitting enzyme apyrase, and by monospecific antifibrinogen Fab fragments. The synthetic peptide analog of the platelet receptor recognition site on the gamma chain of fibrinogen, gamma 400-411, inhibited platelet aggregation induced by mutant Re595 (IC50 160 mumol/L), whereas serotonin secretion was unaffected. Tetrapeptide, RGDS, analogous to human fibrinogen alpha chain (alpha 572-575) and to the cell adhesion site of fibronectin, also inhibited aggregation induced by mutant Re595 (IC50 60 mumol/L). Secretion of 14C-serotonin was preceded by a very rapid phosphorylation of a platelet protein of mol wt 47,000, which is associated with protein kinase C activation. Myosin light chain (mol wt 20,000) was also phosphorylated. Both phosphoproteins were dephosphorylated while secretion was reaching maximum. Furthermore, release of 3H-arachidonic acid from platelet phospholipids and generation of thromboxane B2 via the cyclooxygenase pathway were observed. Inhibition of this pathway with acetylsalicylic acid (10(-4) mol/L) or indomethacin (5 X 10(-4) mol/L) reduced 14C-serotonin secretion and platelet aggregation. The role of Lipid A in the interaction of mutant Re595 with human platelets was deduced from the inhibitory effect of the Lipid A-binding protein present in Limulus amebocyte lysate. Likewise, polymyxin B, known to complex with Lipid A, was inhibitory. The reactivity of mutant Re595 toward platelets was attenuated by mild acid hydrolysis, during which KDO was dissociated from the glycolipid, and by alkaline hydrolysis, which breaks ester-linked fatty acids in Lipid A. In contrast to mutant Re595, strain S218 of S minnesota bearing "complete" endotoxic lipopolysaccharide did not induce secretion and aggregation of human platelets.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of human platelet activation by endotoxic glycolipid-bearing mutant Re595 of Salmonella minnesota. 376 28


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