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)

Prostaglandin (PG) release is characteristic of most inflammatory diseases. The committed step in the formation of free arachidonic acid into PG products is catalyzed by cyclooxygenase (COX, prostaglandin H2 synthase, PGHS), which exists as two genetically distinct isoforms. COX-1 is constitutively expressed and produces PGs and thromboxane A2 during normal physiologic activities, while COX-2 is an inducible enzyme stimulated by growth factors, lipopolysaccharide, and cytokines during inflammation or cell injury. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) released into the amniotic fluid in the setting of infection have been proposed to signal amnion and decidual cells to produce PGs that may culminate in preterm labor. However, since the molecular control of this phenomenon has not been established, this study used amnion-derived WISH cells to determine if TNF-alpha promoted the formation of PGs through COX-2 activity. Treatment of WISH cells with TNF-alpha (0.1 ng/mL-100 ng/mL) caused a dose-dependent increase in COX-2 expression and the subsequent biosynthesis of PGE2 that persisted for at least 48 hrs. In contrast, COX-1 mRNA and protein levels were unaltered by TNF-alpha treatment as determined by RT-PCR and immunoblot analysis, respectively. TNF-alpha-stimulated COX-2 expression and the subsequent formation of PGE2 were inhibited by dexamethasone (0.1 microM). In addition, indomethacin (1 microM) and the novel COX-2-selective inhibitor, NS-398 (IC50 approximately 1.1 x 10(-9) M), attenuated TNF-alpha-elicited PGE2 production. Results presented here demonstrate that TNF-alpha elicits prolonged and regulatable induction of COX-2 in WISH cells, while COX-1 is constitutively expressed and unchanged in response to TNF-alpha stimulation.
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PMID:Tumor necrosis factor-alpha promotes sustained cyclooxygenase-2 expression: attenuation by dexamethasone and NSAIDs. 944 Jan 35

We have evaluated the selectivity in vitro of various conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and new anti-inflammatory compounds (NS-398, L-745,337 and SC58125) in inhibiting the cyclooxygenase activity of platelet prostaglandin endoperoxide synthase (PGHS)-1 and monocyte PGHS-2 in a human whole blood assay. The effects of the compounds towards the cyclooxygenase activity of monocyte PGHS-2 induced in response to lipopolysaccharide (LPS) was evaluated by measuring the levels of PGE2 produced in plasma. The effects of the same inhibitors on platelet PGHS-1 activity were assessed by allowing 1-ml whole blood samples to clot at 37 degrees C for 1 h in the presence of the compounds and measuring immunoreactive TXB2 levels in serum. Under these experimental conditions, most compounds resulted equipotent towards the two isozymes. Differently, meloxicam, nimesulide and diclofenac were approximately 10- to 20-fold more potent in inhibiting the cyclooxygenase activity of monocyte PGHS-2 than platelet PGHS-1. L-745,337, NS-398 and SC58125 achieved selective inhibition of monocyte PGHS-2 (IC50, PGHS-1/IC50, PGHS-2: < 100) and may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to human inflammatory disease and to verify the hypothesis that the common side-effects of NSAIDs are due primarily to their ability to affect the activity of PGHS-1.
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PMID:Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs. 944 11

The aim of this study was to investigate the influence of the acute-phase response and the proinflammatory cytokines on the transcription of the genes encoding the limiting enzymes for the production of prostaglandins, cyclooxygenase (COX)-1 and COX-2, in the rat brain. The bacterial endotoxin lipopolysaccharide (intravenous and intraperitoneal) and turpentine (intramuscular) were used as different models of inflammation in adult male rats. Animals were also killed at various times after intravenous administration of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6, and mRNAs encoding COX-1 and COX-2 were assayed by in situ hybridization histochemistry. A profound transcriptional activation of the gene encoding COX-2 was detected over blood vessels of the entire brain microvasculature, choroid plexus, and leptomeninges of lipopolysaccharide-challenged rats. Injection of the endotoxin intravenously also increased COX-2 gene expression within parvocellular division of the hypothalamic paraventricular nucleus. It is interesting that intramuscular turpentine injection stimulated transcription of COX-2 along endothelium of brain capillaries, and the signal of this transcript paralleled the inflammation of the left hind limb. A robust COX-2 mRNA signal was detected rapidly in the brain microvessels of interleukin-1beta-injected rats, whereas tumor necrosis factor-alpha administration caused a modest but significant induction of this transcript. In contrast, intravenous injection of interleukin-6 did not alter genetic expression of COX-2, and none of the above described models affected the synthesis of COX-1 gene in the rat brain. These results indicate that specific cell populations, in particular vascular- and/or perivascular-associated cells, are responsible for the central production of prostaglandins during systemic inflammation, and circulating interleukin-1beta is likely to be a potent mediator of this response.
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PMID:Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. 945 38

We have synthesized more than 80 novel triterpenoids, all derivatives of oleanolic and ursolic acid, as potential anti-inflammatory and chemopreventive agents. These triterpenoids have been tested for their ability to suppress the de novo formation of two enzymes, inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), using IFN-gamma-stimulated primary mouse macrophages or lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as assay systems. Two synthetic oleananes, 3,12-dioxoolean-1-en-28-oic acid (TP-69) and 3,11-dioxoolean-1,12-dien-28-oic acid (TP-72), were highly active inhibitors of de novo formation of both iNOS and COX-2. Both TP-69 and TP-72 blocked the increase in iNOS or COX-2 mRNA induced by IFN-gamma or LPS. In addition, TP-72 suppressed NF-KB activation in primary macrophages treated with the combination of IFN-gamma and LPS or IFN-gamma and tumor necrosis factor. The 3-alpha(axial)-epimer of ursolic acid suppressed de novo formation of COX-2, in contrast to naturally occurring 3-beta(equatorial)-ursolic acid. Inhibitory effects of TP-69 or TP-72 on iNOS formation were not blocked by the glucocorticoid receptor antagonist RU-486, indicating that these triterpenoids do not act through the glucocorticoid receptor, nor does TP-72 act as an iNOS or COX-2 enzyme inhibitor when added to RAW cells in which synthesis of these two enzymes in response to LPS has already been induced. It may be possible to develop triterpenoids as useful agents for chemoprevention of cancer or other chronic diseases with an inflammatory component.
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PMID:Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. 948 26

Pre-exposure of THP-1 cells to low concentrations of endotoxin (lipopolysaccharide, LPS) down-regulates thromboxane (Tx) A2, an arachidonic acid (AA) metabolite, production in response to a subsequent LPS stimulation. To further delineate the mechanisms of LPS-induced down-regulation of TxA2, we examined expression of prostaglandin H synthase (PGHS)-2 mRNA, changes in PGHS activity, and content of PGHS-1 and -2. Pre-exposure to LPS (1 microg/mL for 18 h to desensitize cells) inhibits production of TxB2, the stable metabolite of TxA2, in response to secondary stimulation of LPS (10 microg/mL), when compared with LPS-stimulated naive cells (p < .05, n=5). LPS (10 microg/mL) induced expression of PGHS-2 mRNA at 1 and 2 h in naive cells, but this expression was decreased in the LPS-desensitized cells. However, exogenous AA (16 microM) or phorbol myristic acid (PMA), 3 microM) stimulated greater TxB2 production in the LPS-desensitized cells than in the naive cells (p < .05). Protein content of PGHS-1 and -2 were examined by Western blot analysis, using antibodies specific for PGHS-1 and PGHS-2. Densitometric analysis demonstrated a significant increase in PGHS-2 induction in LPS-stimulated naive cells (405+/-174%) over its respective basal group (p < .05, n=5). PGHS-1 was constitutively present, but there was no significant difference in quantity between naive and LPS-desensitized basal or LPS-stimulated groups. Thus, despite the reduction in expression of PGHS-2 mRNA, these composite data demonstrate that down-regulation of PGHS activity (assessed with exogenous AA or PMA) cannot be responsible for the inhibition of AA metabolism observed in LPS desensitization.
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PMID:Suppressed thromboxane production in endotoxin-desensitized THP-1 cells is not a result of decreased prostaglandin H synthase activity. 961 86

Emerging evidence has suggested the pivotal role of mast cells in a host defense against bacterial infection. In this paper, we report that bacterial lipopolysaccharide (LPS) is a potent enhancer of the cytokine- and IgE-dependent delayed responses of IL-3-dependent mouse bone marrow-derived cultured mast cells (BMMC). LPS, although showing minimal effects, significantly augmented the c-kit ligand (KL)- or IgE-dependent expression of cyclooxygenase (COX)-2 and the attendant delayed PGD2 generation, with IL-10 and IL-4 acting as potentiating and inhibitory cytokines, respectively. The COX-2-inducing activity of LPS was mimicked by exogenous IL-1 beta. Assessment of endogenous cytokine induction revealed that IL-1 beta expression was stimulated by either LPS or exogenous IL-1 beta. IL-6 expression occurred in parallel with COX-2 expression. IL-10 expression, which lagged behind COX-2 expression, depended on exogenous IL-10, but not on LPS and IL-1 beta. Thus, LPS and IL-1 beta exhibited similar biological activities in terms of COX-2 and endogenous cytokine expression. However, adding an antibody against the type I IL-1 receptor to BMMC, which abrogated the effects of IL-1 beta, failed to neutralize the effects of LPS. These results suggest that LPS activates BMMC through the signal transduction pathway shared with exogenous IL-1 beta, rather than exerting its action indirectly via the production of endogenous IL-1 beta.
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PMID:Regulation of cyclooxygenase-2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c-kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells. 963 92

Secretory phospholipase A2 (sPLA2) is the major effector involved in arachidonic acid (AA) mobilization and prostaglandin E2 (PGE2) production during stimulation of P388D1 macrophages with the inflammatory stimuli bacterial lipopolysaccharide and platelet-activating factor. We herein demonstrate that PGE2 in stimulated P388D1 cells is accounted for by the inducible cyclooxygenase (COX)-2. COX-1, though present, appears not to participate significantly in stimulus-induced PGE2 production in P388D1 macrophages. Reconstitution experiments utilizing exogenous recombinant sPLA2 demonstrate that activation of the sPLA2 at the plasma membrane is highly dependent on previous activation of the cytosolic phospholipase A2 (cPLA2). Collectively these results demonstrate (i) that functional coupling exists between sPLA2 and COX-2 in activated cells, (ii) the critical role that cPLA2 plays in lipid mediator production, and (iii) that there is crosstalk between cPLA2 and sPLA2 in the cell.
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PMID:Functional coupling between secretory phospholipase A2 and cyclooxygenase-2 and its regulation by cytosolic group IV phospholipase A2. 965 21

We investigated the role of prostaglandin E2 (PGE2) and its interactions with nitric oxide (NO) on cell death and NO-mediated cytotoxicity in the murine macrophage cell line J774. Stimulation of the J774 cells with lipopolysaccharide together with interferon-gamma resulted in a dose-dependent cytotoxicity and production of PGE2 and NO, measured as nitrite. Our results showed a linear correlation between PGE2 release and cytotoxicity. The cyclooxygenase (COX) inhibitor indomethacin completely inhibited PGE2 biosynthesis, without affecting NO production or cell death. This supports previous reports suggesting that overproduction of endogenous PGE2 is mainly the consequence of cell death and does not cause it. In contrast, the NO synthase inhibitor N(omega)-monomethyl-L-arginine (L-NMMA) gave a significant, though incomplete suppression of NO release and cell death. This points to the presence of other cytotoxic factors besides NO. To evaluate the toxic effect solely due to NO, macrophages were exposed to the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Incubation with SNAP also resulted in a concentration-dependent cell injury and PGE2 production. When exogenously added, PGE2 protected against SNAP-mediated cytotoxicity and simultaneously increased PGE2 release into the medium, without inducing COX-2. The cytoprotection and the stimulation of PGE2 release were both reversed by indomethacin. In conclusion, PGE2 biosynthesis may represent a mechanism by which inflammatory macrophages protect themselves against the cytotoxic effects of NO.
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PMID:The role of prostaglandin E2 and nitric oxide in cell death in J774 murine macrophages. 967 Nov 12

Macrophages exudating into inflammatory sites (thioglycollate-elicited macrophages, TGM) have a diminished ability to synthesize prostaglandins (PG) as compared with resident peritoneal macrophages (RM). Constitutive expression of cyclooxygenase-1 (COX-1) was lower in TGM than in RM but the releasability of arachidonic acid was not significantly different. Thus, the differences in expression of COX-1 were primarily responsible for the abilities of TGM and RM to synthesize PGE2 upon calcium ionophore (CaI) stimulation. COX-1 expression in RM and TGM was also correlated with their ability to synthesize PGE2 from exogenously added arachidonic acid. When exposed to lipopolysaccharide (LPS), the induction of COX-2 and the enhancement of PGE2 synthesis upon CaI were much lower in TGM as compared with RM the releasability of arachidonic acid upon CaI stimulation was relatively unchanged in RM but was reduced in TGM Thus, in TGM as compared with RM, a lower level of COX-1 expression and a lower level of COX-2 induction, and the reduction of arachidonate releasability by LPS exposure, are mainly responsible for lower PGE2 synthetic ability upon CaI stimulation. However, the different COX-2 induction by LPS in RM and TGM was not reflected in their increase in the ability to synthesize PGE2 from exogenously added arachidonic acid.
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PMID:Absence of relation between the expression of cyclooxygenase isoforms and the synthesis of prostaglandin E2 in resident and thioglycollate-elicited macrophages in rats. 967 17

Although the severity of periodontal disease is known to be affected by age, functional changes of periodontal tissue cells during the aging process are not well characterized. It is important to define how cellular aging affects the progression of periodontal diseases associated with the aging process. In vitro aging of human gingival fibroblast (HGF) and periodontal ligament fibroblast (HPLF) cells was prepared by sequential subcultivations (5 to 6 passages as young, 18 to 20 passages as old). GFs were also prepared from gingiva of Down's syndrome patients and 60-week-old rats. Fetal rat calvarial osteoblasts were prepared by sequential digestion with collagenase. HGF and HPLF cells were treated with lipopolysaccharide (LPS) and cyclic tension force, respectively. Amounts of PGE2, interleukin (IL)-1 beta, IL-6, and plasminogen activator (PA) in conditioned media were measured. Total RNA was extracted, and mRNA expression was analyzed by reverse transcription polymerase chain reaction (RT-PCR). LPS-stimulated PGE2, IL-1 beta, IL-6, and PA production was increased in "old" HGF compared to younger cells. According to RT-PCR analysis, gene expression of COX-2, IL-1 beta, IL-6, and tissue type (t) PA was higher in old cells than in young cells. Cyclic tension force to HPLF also stimulated phenotypic and gene expression of IL-1 beta, PGE2 (COX-2 gene) and tPA. These findings suggest that aging in both HGF and HPLF may be an important factor in the severity of periodontal disease through higher production of inflammatory mediators in response to both LPS and mechanical stress. In addition, oxygen radical-treated fibronectin (FN) as substratum diminished bone nodule formation by osteoblasts when compared with intact FN. This finding suggests that FN plays an important role in Osteoblast activity and that FN damaged by oxygen radicals during the aging process may be related to less bone formation.
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PMID:Effect of aging on functional changes of periodontal tissue cells. 972 19


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