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 determine how aspirin intake might influence lipopolysaccharide (LPS)-induced tissue factor (TF) activity and tumour necrosis factor (TNF) in human blood monocytes, we collected blood before and at various times after intake of 300 mg aspirin in 25 healthy volunteers. Aspirin intake reduced LPS-induced thromboxane B2 and PGE2 production in whole blood by 50% and 65% respectively, measured 1 h after aspirin intake. Subsequently, a 95% rise in LPS-induced TF activity in monocytes was seen as compared to a 26% rise in TNF. The rise in TF activity was maximal within 1 h after aspirin intake and no further rise was observed 3, 4 or 24 h after aspirin intake. In contrast, TF activity induced by incubating whole blood in the absence of LPS fell rapidly after the intake of aspirin. In separate experiments, a dose-dependent inhibition by PGE2 was observed in LPS-induced TF activity in monocytes. It is proposed that the increased LPS-induced TF activity and TNF production following aspirin intake may be due to suppressed PGE2 formation. The more pronounced rise in TF activity compared to TNF production may be due to an enhancement of the platelet lipoxygenase pathway that has been shown to be important for LPS-induced TF activity in monocytes.
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PMID:Increased lipopolysaccharide-induced tissue factor activity and tumour necrosis factor production in monocytes after intake of aspirin: possible role of prostaglandin E2. 164 9

The effects of cyclo-oxygenase inhibitors on interleukin-6 (IL-6) production by human peripheral blood mononuclear cells were examined. Indomethacin and Y-9223, a novel cyclo-oxygenase inhibitor, inhibited the increases in the IL-6 level in the culture medium of both mitogen-stimulated adherent cells and non-adherent cells fractionated from mononuclear cells. Northern blotting showed that the mitogen-induced increase in the expression of IL-6 mRNA was inhibited by indomethacin and Y-9223, indicating that these agents inhibit IL-6 biosynthesis. Aspirin, ibuprofen, and phenylbutazone also inhibited IL-6 production by adherent cells stimulated with lipopolysaccharide (LPS). There was, however, no direct relationship between inhibition of IL-6 and prostaglandin E2 (PGE2) production by these agents. The addition of PGE2 corresponding to the amount produced by adherent cells stimulated with LPS slightly increased IL-6 production by unstimulated adherent cells, but to a lower level than that reached with LPS. An anti-PGE2 antibody partially blocked IL-6 production by adherent cells stimulated with LPS. These results suggest that, in addition to the inhibition of PGE2 production, other mediators including cyclooxygenase products or other action mechanisms are involved in the inhibition of IL-6 production by these drugs.
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PMID:Inhibition by cyclo-oxygenase inhibitors of interleukin-6 production by human peripheral blood mononuclear cells. 181 50

The cloned interleukin-3 dependent cell line, M1-A5 was studied to determine whether protein kinase C, calcium mobilization, and 5-lipoxygenase activity were involved in the signal transduction pathways required for the production of TNF. TNF release was stimulated by 10 ng/ml phorbol myristate acetate (PMA), 2 microM calcium ionophore A23187, and 1 microgram/ml lipopolysaccharide (LPS) with synergism seen between PMA and A23187. All signals were blocked by phloretin and the PMA signal was blocked by H-7, both drugs acting as protein kinase C inhibitors. Desensitization of protein kinase C by PMA (1 microgram/ml for 24 h) provided evidence that both PMA- and LPS-stimulated TNF production were protein kinase C-dependent while A23187-stimulated TNF production was not. Both the calcium chelator, EGTA, and the intracellular calcium antagonist, TMB-8, inhibited TNF production stimulated by all agents, indicating that TNF stimulation by all agents was calcium dependent. Finally, the 5-lipoxygenase inhibitors, ketoconazole and L-656,224, but not the cyclo-oxygenase inhibitor ASA, inhibited TNF stimulated by all agents. These findings indicate that, although TNF production by M1-A5 cells can be stimulated either by a calcium/protein kinase C- or by a calcium-dependent signal, there is a convergence of signals at the level of 5-lipoxygenase activation.
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PMID:The involvement of protein kinase C, calcium, and 5-lipoxygenase in the production of tumor necrosis factor by a cloned interleukin-3 dependent cell line with natural cytotoxic activity. 190 37

The effects of sulphasalazine (SASP), sulphapyridine (SP), and 5-aminosalicylic acid (5-ASA) have been studied on mouse spleen cells cultured in the presence of phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and lipopolysaccharide (LPS). SASP exhibited a significant degree of suppression, at doses in the range 25-100 micrograms/ml (p less than 0.01), this suppression being greater than 50% at 50 micrograms/ml. SP exhibited only a minor degree of suppression (10% at 75 micrograms/ml, p less than 0.01). Coadministration of a non-steroidal anti-inflammatory drug (NSAID), indomethacin, produced no evidence of further suppression in the presence of SASP or SP. Administration of SP plus 5-ASA to parallel cultures that were profoundly suppressed by the molecular equivalent amount of SASP resulted in no suppression. This implied requirement of the intact parent molecule (SASP) to produce this effect, at these concentrations. The concentration of SASP required to produce more than 50% suppression was higher than that ever attained in the peripheral blood of humans receiving therapeutic doses of the drug. Human lymphocytes are similarly suppressed by SASP, but only at higher concentrations than are required for murine cells. Thus, if the parent drug is the active moiety and requires these concentrations to be effective in vivo, it follows that the site where these effects may be mediated is likely to be the intestinal tract. The effects described would suggest the gut associated lymphoid tissue as a likely target.
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PMID:Effect of sulphasalazine and its metabolites on mitogen induced transformation of lymphocytes--clues to its clinical action? 290 97

The hypothesis was tested that vitamin E protects chickens from a lethal Escherichia coli infection by inhibiting the biosynthesis of prostaglandins, thereby activating humoral immunity and phagocytosis. When chickens were fed supplement vitamin E at the level of 300 mg/kg diet, which is six times the presently used dietary level, endogenous PGE1, PGE2, and PGF2 alpha levels decreased in the immunopoietic organs, bursa, and spleen. Antibody titers to E. coli lipopolysaccharide and phagocytosis increased at the same time. Infection slightly increased prostaglandin levels and vitamin E appeared to compensate for this increase. Aspirin, a known prostaglandin inhibitor acted synergistically with vitamin E in depressing endogenous PG levels in bursa and decreasing mortality from E. coli infection.
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PMID:Vitamin E and aspirin depress prostaglandins in protection of chickens against Escherichia coli infection. 701 Sep 85

Nitric oxide synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation in rheumatic and autoimmune diseases. We report that exposure of lipopolysaccharide-stimulated murine macrophages to therapeutic concentrations of aspirin (IC50 = 3 mM) and hydrocortisone (IC50 = 5 microM) inhibited the expression of iNOS and production of nitrite. In contrast, sodium salicylate (1-3 mM), indomethacin (5-20 microM), and acetaminophen (60-120 microM) had no significant effect on the production of nitrite at pharmacological concentrations. At suprapharmacological concentrations, sodium salicylate (IC50 = 20 mM) significantly inhibited nitrite production. Immunoblot analysis of iNOS expression in the presence of aspirin showed inhibition of iNOS expression (IC50 = 3 mM). Sodium salicylate variably inhibited iNOS expression (0-35%), whereas indomethacin had no effect. Furthermore, there was no significant effect of these nonsteroidal anti-inflammatory drugs on iNOS mRNA expression at pharmacological concentrations. The effect of aspirin was not due to inhibition of cyclooxygenase 2 because both aspirin and indomethacin inhibited prostaglandin E2 synthesis by > 75%. Aspirin and N-acetylimidazole (an effective acetylating agent), but not sodium salicylate or indomethacin, also directly interfered with the catalytic activity of iNOS in cell-free extracts. These studies indicate that the inhibition of iNOS expression and function represents another mechanism of action for aspirin, if not for all aspirin-like drugs. The effects are exerted at the level of translational/posttranslational modification and directly on the catalytic activity of iNOS.
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PMID:The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. 754 10

1. The non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, 10 and 100 microM, piroxicam, 100 microM, and sodium meclofenamate, 1 and 100 microM, potentiated the lipopolysaccharide (LPS)-stimulated release of interleukin-1 (IL-1)-like activity from mouse peritoneal macrophages. Aspirin up to 100 microM was without effect. The drugs did not themselves stimulate the release of IL-1-like activity at the concentrations used. 2. LPS, 1 microgram ml-1, stimulated prostaglandin E2 production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 microM, indomethacin, 1 microM, piroxicam, 10 microM and sodium meclofenamate, 0.1 microM. 3. The potentiation of LPS-stimulated release of IL-1-like activity produced by indomethacin, 100 microM, piroxicam, 100 microM, or sodium meclofenamate, 10 microM, was inhibited by prostaglandin E2, (PGE2) 10 ng ml-1. 4. Aspirin, 100 microM, indomethacin, 100 nM to 10 microM, piroxicam, 1 to 100 microM, and sodium meclofenamate, 10 nM, all potentiated cell-associated IL-1-like activity in LPS- stimulated macrophages. The drugs had no effect on cell-associated IL-1-like activity by themselves. 5. Exogenous PGE2, 2 to 30 ng ml-1, inhibited the cell-accumulation of IL-1-like activity stimulated by LPS in the presence of indomethacin, 1 microM, or sodium meclofenamate, 0.1 microM. 6. The 5-lipoxygenase inhibitors BWA4C, 0.01 to 10 microM, and L-651,392, 0.01 to 10 microM, had no effect on LPS-stimulated released or cell-associated IL-1-like activity. Over the same concentration-ranges,neither of the 5-lipoxygenase inhibitors affected released or cell-associated IL-1-like activity in LPS stimulated mouse macrophages in the presence of indomethacin, 1 JM.7. The synthetic diacylglycerol, DiC8, 10 to 200 JAM, did not itself increase released or cell-associated IL-I-like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 JM, DiC8increased released and cell-associated IL-i-like activity. The activity of DiC8 on released and cell associated IL-l-like activity was not increased by indomethacin, 100 micro M.8. NSAIDs increase LPS-induced cell-associated IL-i-like activity in mouse macrophages by inhibiting the formation of cyclo-oxygenase products such as PGE2 but at higher concentrations the NSAIDs potentiate LPS-induced release of IL-I-like activity by a mechanism independent of cyclo-oxygenase inhibition. The potentiation of the release of IL-i-like activity appears not to be related to an effect of NSAIDs on either 5-lipoxygenase or diacylglycerol metabolism.
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PMID:The effect of non-steroidal anti-inflammatory drugs on the accumulation and release of interleukin-1-like activity by peritoneal macrophages from the mouse. 785 71

Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.
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PMID:Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia. 802 33

The influence of analgesics at low concentrations on permeability and beta-lactamase expression have been studied "in vitro". The effect of these drugs on major outer membrane proteins and the lipopolysaccharide was evaluated. Acetylsalicylate and paracetamol induced modifications in susceptibility to a large variety of antibiotics when tested at therapeutic concentrations. The results suggested that when analgesics and antibiotics are administered simultaneously, the interaction between both kinds of drugs can alter the response of microorganisms to antibiotics.
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PMID:Modification by analgesics of the susceptibility to antibiotics in Serratia marcescens. 859 Mar 91

Aspirin and sodium salicylate each inhibit to a similar extent the production of nitric oxide (NO) in the RAW 264.7 murine macrophage cell line following stimulation by either lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma). The similar potencies of aspirin and sodium salicylate indicate that acetylation of cellular macromolecules is not essential for the observed effects. The failure of added prostaglandin E2 to overcome the effects of aspirin or sodium salicylate indicates that these effects are not simply the result of inhibition of prostaglandin synthesis. The inhibition of NO production occurs irrespective of the effect of these agents on induction of nitric oxide synthase (iNOS) mRNA by LPS or IFN-gamma. Aspirin and sodium salicylate inhibit iNOS mRNA induction in LPS-stimulated cells but enhance iNOS mRNA induction in IFN-gamma-stimulated cells. In contrast, these agents consistently inhibit induction of argininosuccinate synthetase mRNA in both LPS- and IFN-gamma-stimulated cells. Concentrations of aspirin in the 3-10 mM range inhibit induced NO production and expression of iNOS protein without inhibiting induction of iNOS mRNA. Discordances between effects on NO synthesis and induction of iNOS mRNA indicate that aspirin and sodium salicylate have multiple sites of action in their effects on pathways that are involved in the production of NO by stimulated RAW 264.7 cells.
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PMID:Novel actions of aspirin and sodium salicylate: discordant effects on nitric oxide synthesis and induction of nitric oxide synthase mRNA in a murine macrophage cell line. 869 Oct 69


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