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)

Reports from several laboratories have suggested that interleukin 6 (IL-6) may play a role in the process of bone resorption. We have extended these studies by examining the role of IL-6 in fetal rat long bone (FRLB) resorption stimulated by a variety of agents, including parathyroid hormone (PTH); 1,25 dihydroxyvitamin D3 (1,25(OH)2D3); interleukin 1 (IL-1); tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS). This model of bone resorption does not require the generation of osteoclasts in order to elicit a resorptive response and allowed us to assess whether IL-6 can directly affect osteoclastic bone resorption. We confirmed previous studies which showed that exogenous recombinant murine or human IL-6 does not stimulate bone resorption and demonstrated that IL-6, when added prior to the addition of parathyroid hormone, caused a significant but somewhat variable inhibition at 120 hours. Exogenous PGE2 stimulated both IL-6 production and resorption in FRLB cultures in a concentration-dependent manner. Endogenous production of IL-6 in fetal rat long bone (FRLB) cultures was stimulus dependent and generally correlated with prostaglandin E2 (PGE2) levels in the same cultures. However, endogenous IL-6 production did not correlate with the extent of bone resorption, except when IL-1 and PGE2 were used as stimuli. Addition of indomethacin and diclofenac to IL-1 stimulated cultures demonstrated that both the IL-6 production and bone resorption were largely PGE-2 dependent. Neutralizing anti-IL-6 antibodies inhibited IL-6 activity in FRLB cultures but did not affect bone resorption, even in the IL-1 stimulated cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin 6 production in fetal rat long bone cultures is correlated with PGE2 release and does not correlate with the extent of bone resorption. 794 44

To better understand the effects of freezing on various immunocompetent cell functions, the interleukin-6 (IL-6)-producing activities of frozen peripheral blood mononuclear cells (PBMCs) from healthy subjects were determined. Frozen, lipopolysaccharide (LPS)-activated PBMCs produced significantly larger quantities of IL-6 than fresh cells. Although elimination of radiosensitive, CD8+ suppressor T cells had no significant effect on PHA-induced IL-6 production by T cells, elimination of CD4+ Leu-8+ suppressor T cell subsets resulted in a significantly enhanced IL-6 secretion. Exogenous addition of prostaglandin E-2 to frozen PBMCs and monocytes inhibited LPS-induced IL-6 production. The results suggest that functional inactivation of a subset of cryosensitive, PGE-2-secreting monocytes is associated with an increase in IL-6 production by the other subset. They also indicate that a subset of CD4+ Leu-8+ T cells might be involved in feedback inhibition of PHA-induced T cell-mediated IL-6 production. The results provide further evidence that the presence of larger quantities of IL-6 in conjunction with increased amounts of IL-1 and IL-2 secreted by the frozen cells may be responsible for the previously reported enhanced immunoglobulin-producing abilities of frozen cells from clinically healthy subjects and from patients with lung cancer.
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PMID:Effects of cryopreservation on immune responses: VII. Freezing induced enhancement of IL-6 production in human peripheral blood mononuclear cells. 798 56

Cyclo-oxygenase, a key enzyme in prostaglandin production, is mainly in the constitutive form (COX-1) in gastric mucosa, whereas leucocytes have an inducible enzyme (COX-2). We report that indomethacin and its glycolic acid ester acemetacin have quantitatively different effects on prostanoid synthesis in these tissues. Human gastric mucosa (fresh operation specimens, cut finely and washed), and 1-1.5 x 10(6) human blood leucocytes stimulated with lipopolysaccharide (5 micrograms/ml), were incubated with acemetacin or indomethacin (0.1, 1, 10, 100 micrograms/ml). Eicosanoids in the medium were measured by radioimmunoassay (RIA). In leucocytes, acemetacin and indomethacin were more potent cyclo-oxygenase inhibitors than in the gastric mucosa, and both reduced the PGE levels to similar extents (70-98% and 72-100% respectively, n = 5). LTB4 was reduced only at 100 micrograms/ml of either drug. In gastric mucosal incubates, acemetacin was less potent than indomethacin in causing a concentration-related inhibition of PGE accumulation (19-74% vs 34-84%; n = 6, p < 0.05). Acemetacin was also less potent than indomethacin in reducing gastric 6-keto-PGF1 alpha and TXB2 (by 11-79% vs 45-72%, and 0-80% vs 29-80% respectively, p < 0.05). The finding that acemetacin is equipotent to indomethacin on leucocyte cyclo-oxygenase (inducible enzyme, COX-2) but less active on the gastric mucosa (COX-1) is consistent with an effective analgesic and anti-inflammatory activity of acemetacin coupled with better gastric tolerance than that to indomethacin.
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PMID:Acemetacin and indomethacin: differential inhibition of constitutive and inducible cyclo-oxygenases in human gastric mucosa and leucocytes. 814 13

In rats with CCl4-induced liver cirrhosis, a twofold decrease of blood clearance rate and a fourfold reduction in number of Kupffer cells taking up colloidal carbon particles has been demonstrated. Zymosan stimulation does not lead to granuloma-like structures in the liver of CCl4-cirrhotic rats. In cirrhotic rats, unlike controls, the cathepsin D activity of liver tissue is very little increased by zymosan treatment and there is virtually no increase in collagenolytic activity. The increase in PGE content in cirrhotic rat liver after prodigiosan stimulation was 2.5 times less than in stimulated control animals. In cirrhotic rats, the IL-1 producing capacity of blood monocytes in vitro in response to lipopolysaccharide drops almost fivefold. The total count of bone marrow-derived myeloid colonies in cirrhotic zymosan-stimulated animals was reduced by 1.5-fold whereas in control animals zymosan induced a 1.8-fold increase in the number of myeloid colonies. The number, uptake and nitroblue tetrazolium-reducing capacities of lung, spleen, peritoneal and bone marrow macrophages in animals with liver cirrhosis were only slightly increased in response to zymosan as compared to control animals. The low response of extrahepatic macrophages to stimuli in cirrhotic animals is thought to be due to their premobilization during the development of cirrhosis.
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PMID:Mononuclear phagocyte system responsiveness in CCl4-induced liver cirrhosis. 833 74

Prostaglandins are pro-inflammatory but are gastroprotective. The gastric mucosa synthesizes prostaglandins mainly via constitutive cyclooxygenase (COX-1), whereas leucocytes have inducible enzyme (COX-2). Nimesulide (CAS 51803-78-2) differentially inhibited prostanoid synthesis in these human tissues as well as with in vitro enzyme assays, and was less potent than indometacin (CAS 53-86-1) on COX-1. Fresh human gastric mucosa was cut finely, washed and pre-incubated (100 mg in 1 ml phosphate buffered saline pH 7.4) with or without nimesulide or indometacin (0.1-100 micrograms/ml; 0 degree C; 30 min). The fluid was replaced with fresh identical solution, incubated (37 degrees C; 30 min) and the solution assayed. Isolated leucocytes from human peripheral blood were incubated (1-1.5 x 10(6), 2 ml Krebs' solution) with or without nimesulide or indometacin (0.1-100 micrograms/ml; 37 degrees C; 1 h), stimulated with lipopolysaccharide (5 micrograms/ml), further incubated for 24 h at 37 degrees C and the medium assayed for the prostanoids PGE, TXB2, 6-keto-PGF1 alpha and the leukotriene LTB4 by radioimmunoassay (RIA). In vitro assays with COX-1 from ram seminal vesicles, or COX-2 from sheep placenta, were performed by pre-incubating the enzymes with vehicle alone (controls) or with drug for 5 min at 37 degrees C. Arachidonate (10 mumol/l) was added and further incubated for 2 min at 37 degrees C. Reactions were terminated and PGE determined by RIA. Both drugs caused concentration-related inhibitions of prostanoid accumulation in incubates of both tissues. Nimesulide reduced PGE accumulation more potently in incubates of stimulated leucocytes than of gastric mucosa. With gastric tissue, nimesulide was less potent than indometacin by approximately 6-22 fold (IC50 for PGE, TXB2, 6-keto-PGF1 alpha, respectively; 14.8 vs 2.5; 12.8 vs 1.0; 31.1 vs 1.4 mumol/l; p < 0.05 to 0.02). With the leucocytes, the concentrations of both drugs, particularly indometacin were not low enough to calculate the IC50. With the in vitro assay, nimesulide (0.01 to 100 mumol/l) did not inhibit PGE formation by COX-1 but caused a concentration-related inhibition of PGE formation by COX-2 (4-60%). These results are consistent with the effective analgesic/anti-inflammatory activity of nimesulide coupled with better gastric tolerance compared to indometacin.
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PMID:Activity of nimesulide on constitutive and inducible cyclooxygenases. 859 66

We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1 beta and TNF synthesis induced by exogenous IL-1 alpha was elevated threefold compared to the pre-aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS- or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1 alpha-induced synthesis of IL-1 beta was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE2-mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.
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PMID:Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo. 869 89

Fever, a hallmark of disease, is elicited by exogenous pyrogens, that is, cellular components, such as lipopolysaccharide (LPS), of infectious organisms, as well as by non-infectious inflammatory insults. Both stimulate the production of cytokines, such as interleukin (IL)-1beta, that act on the brain as endogenous pyrogens. Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis, it is thought that a prostaglandin is important in fever generation. Prostaglandin E2 (PGE2) may be a neural mediator of fever, but this has been much debated. PGE2 acts by interacting with four subtypes of PGE receptor, the EP1, EP2, EP3 and EP4 receptors. Here we generate mice lacking each of these receptors by homologous recombination. Only mice lacking the EP3 receptor fail to show a febrile response to PGE2 and to either IL-1beta or LPS. Our results establish that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP3 receptor.
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PMID:Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. 975 Oct 56

Prostaglandins (PGs) are potent modulators of brain function under normal and pathological conditions. The diverse effects of PGs are due to the various actions of specific receptor subtypes for these prostanoids. Recent work has shown that PGE2, while generally considered a proinflammatory molecule, reduces microglial activation and thus has an antiinflammatory effect on these cells. To gain further insight to the mechanisms by which PGE2 influences the activation of microglia, we investigated PGE receptor subtype, i.e., EP1, EP2, EP3, and EP4, expression and function in cultured rat microglia. RT-PCR showed the presence of the EP1 and EP2 but not EP3 and EP4 receptor subtypes. Sequencing confirmed their identity with previously published receptor subtypes. PGE2 and the EP1 agonist 17-phenyl trinor PGE2 but not the EP3 agonist sulprostone elicited reversible intracellular [Ca2+] increases in microglia as measured by fura-2. PGE2 and the EP2/EP4-specific agonists 11-deoxy-PGE1 and 19-hydroxy-PGE2 but not the EP4-selective agonist 1-hydroxy-PGE1 induced dose-dependent production of cyclic AMP (cAMP). Interleukin (IL)-1beta production, a marker of activated microglia, was also measured following lipopolysaccharide exposure in the presence or absence of the receptor subtype agonists. PGE2 and the EP2 agonists reduced IL-1beta production. IL-1beta production was unchanged by EP1, EP3, and EP4 agonists. The adenylyl cyclase activator forskolin and the cAMP analogue dibutyryl cAMP also reduced IL-1beta production. Thus, the inhibitory effects of PGE2 on microglia are mediated by the EP2 receptor subtype, and the signaling mechanism of this effect is likely via cAMP. These results show that the effects of PGE2 on microglia are receptor subtype-specific. Furthermore, they suggest that specific and selective manipulation of the effects of PGs on microglia and, as a result, brain function may be possible.
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PMID:Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1beta production. 993 Jul 28

The stimulation of intestinal epithelial cell cyclooxygenase (COX) enzymes with inflammatory agents and the inhibition of COX-1 and COX-2 enzymes has the potential to increase understanding of the role of these enzymes in intestinal inflammation. The aim of this study was to determine the contributions of COX-1 and -2 to the production of specific prostanoids by unstimulated and stimulated intestinal epithelial cells. Cultured enterocytes were stimulated with lipopolysaccharide (LPS), interleukin-1 (IL-1)beta (IL-1 beta), and calcium ionophore (Ca Ion), with and without COX inhibitors. Valerylsalicylic acid (VSA) was employed as the COX-1 inhibitor, and SC-58125 and NS398 were used as the COX-2 inhibitors. Prostanoids were quantitated by Elisa assay. Western immunoblotting demonstrated the presence of constitutive COX-1 and inducible COX-2 enzyme. Unstimulated prostanoid formation was not decreased by the COX-1 inhibitor. All of the stimulants evaluated increased prostaglandin E2 (PGE2) production. Only Ca Ion stimulated prostaglandin D2 (PGD2) production while IL-1 beta, and Ca Ion, but not LPS, increased prostaglandin F2 alpha (PGF2 alpha) formation. Ca Ion-stimulated prostanoid formation was uniformly inhibited by COX-2, but not COX-1, inhibitors. IL-1 beta-stimulated PGE2 and PGE2 alpha formation was significantly decreased by both COX-1 and COX-2 inhibitors. VSA, in a dose-dependent manner, significantly decreased IL-1 beta-stimulated PGE2 and PGF2 alpha production. Unstimulated prostanoid formation was not dependent on constitutive COX-1 activity. The stimulation of intestinal epithelial cells by Ca Ion seemed to uniformly produce prostanoids through COX-2 activity. There was no uniform COX-1 or COX-2 pathway for PGE and PGF2 alpha formation stimulated by the inflammatory agents, suggesting that employing either a COX-1 or COX-2 inhibitor therapeutically will have varying effects on intestinal epithelial cells dependent on the prostanoid species and the inflammatory stimulus involved.
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PMID:Contribution of cyclooxygenase-1 and cyclooxygenase-2 to prostanoid formation by human enterocytes stimulated by calcium ionophore and inflammatory agents. 999 Jun 76

In mammals, the increased generation of prostaglandins (PG) during the onset of inflammatory responses and activation of immune cell types has been attributed to the induction of a novel cyclo-oxygenase (COX) isoform, termed COX-2, which is distinct from the well-characterized constitutive activity (COX-1). Goldfish (Carassius auratus) macrophages exposed to bacterial lipopolysaccharide and leucocyte-derived macrophage-activating factor(s) showed a significant increase in the generation of the major COX product, PGE2, within the first 6 h of stimulation. The selective COX-2 inhibitor, NS398, inhibited this elevated generation of PGE, whereas the basal level of this product synthesized by unstimulated macrophages was unaffected by such exposure. PGE generation by goldfish macrophages was similarly inhibited by the glucocorticoid, dexamethasone, and an inhibitor of protein synthesis, cycloheximide, suggesting that this stimulation may be due to an inducible enzyme equivalent to mammalian COX-2. The complete coding sequence of rainbow trout (Oncorhynchus mykiss) COX-2 was obtained by PCR. The gene contains a 61 bp 5'-untranslated region (UTR), a 1821 bp open reading frame and a 771 bp 3'UTR containing multiple copies of an mRNA instability motif (ATTTA). The predicted translation product had high homology to known mammalian and chicken COX-2 (83-84%) and COX-1 (77%) sequences. Reverse-transcriptase PCR with cDNA from control and bacterially challenged fish revealed that trout COX-2 expression was not constitutive but could be induced. Overall, these studies show for the first time that the inducible isoform of COX has a long evolutionary history, probably dating back to the evolution of fish over 500 million years ago.
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PMID:Fish macrophages express a cyclo-oxygenase-2 homologue after activation. 1022 70


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