Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resident peritoneal macrophages exposed to inflammatory stimuli (zymosan, lipopolysaccharide (LPS)) represent a widely used model for studying arachidonic acid metabolism and for screening of prostaglandin (PG) synthesis inhibitors. In the present study, cyclooxygenase 1 (COX1) was shown constitutively expressed in mouse adherent and non-adherent macrophages whereas expression of COX2 was observed only in adherent cells, even when cultured in minimal conditions (Ca-, Mg- and serum-free medium). The COX2 expression was amplified by arachidonic acid cascade stimulating agents (Ca, Mg, zymosan) and by LPS in a time-dependant manner; PGE2 by itself amplified LPS-induced COX2 expression. In well-defined experimental conditions of COX2 expression (LPS-stimulated adherent macrophages), we studied specific interactions of some representative anti-inflammatory drugs with COX2 enzymatic activity and expression. By contrast with dexamethasone, which reduced PGE2 release together with a strong reduction of COX2 expression (protein and mRNA), non steroidal anti-inflammatory drugs (NSAIDs) reduced PGE2 synthesis without any effect at the COX2 mRNA level. This reduction of PGE2 production by NSAIDs resulted from either an exclusive enzymatic inhibition (aspirin, NS398, 6-Methoxy naphtyl acetic acid) or an enzymatic inhibition associated with a slight decrease of COX2 protein level (indomethacin). For paracetamol and salicylic acid, two weak inhibitors of COX enzymatic activity, reduction of PGE2 synthesis appeared to be related to reduced level of COX2. These findings show that the macrophage can be used as a cellular model to study specifically COX1 and COX2. In this cell type, COX2 expression is dependent on adhesion, enhanced by stimulation of arachidonic acid metabolism, and auto amplified by PGE2. Furthermore, the results indicate that known NSAIDs differ in their interaction with cyclooxygenase, being able to inhibit either COX2 enzymatic activity, and/or COX2 expression. However, further studies are required to determine the mechanism and the role of COX2 expression during inflammation in vivo, and to define more precisely the best target for new potent and safe NSAIDs.
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PMID:Characterisation of cyclooxygenase 1 and 2 expression in mouse resident peritoneal macrophages in vitro; interactions of non steroidal anti-inflammatory drugs with COX2. 776 5

Cyclooxygenase (COX) is an enzyme involved in the biosynthesis of prostaglandins and is one of the principle targets of non-steroidal anti-inflammatory drugs. Two isoforms of this enzyme are known to exist in the brain; one of these (type 1 COX or COX1) is constitutively expressed, whereas the other form of the enzyme, which is inducible, has been called type 2 COX (COX2). We have used systemic administration of bacterial lipopolysaccharide (LPS) as a model of the acute phase response to study the expression of COX2 in the murine CNS. We observed COX2 expression in neurons of several regions of the normal murine telencephalon. Robust expression of COX2 mRNA was induced in perivascular cells between 45 min and 6 h after LPS injection. The role of prostaglandins produced by these perivascular cells in the cerebral components of the acute phase response remains to be elucidated.
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PMID:Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. 872 76

Portal venous transfusions (PVTs) of blood have been shown to induce significant immunosuppression in animal models of organ transplantation. A proposed mechanism of PVT-induced immunosuppression is via alteration of Kupffer cell arachidonic acid metabolism with increased secretion of the suppressive metabolite prostaglandin E2 (PGE2). This study assessed the hypothesis that PVT increases Kupffer cell PGE2 production via up-regulation of Kupffer cell phospholipase A2 (PLA2) as well as constitutive (COX1) and inducible (COX2) cyclooxygenase. Kupffer cells from Lewis rats were harvested 1 hr after PVT with either 1 ml of Wistar-Furth blood, systemic transfusion (SVT), or saline via portal vein (PVSal). After lipopolysaccharide stimulation, 24-hr Kupffer cell supernatant fractions were assayed for PGE2. PGE2 was increased after SVT (1465+/-234 pg/ml) compared with PVSal (597+/-99; P<0.01). PVT increased Kupffer cell PGE2 (5370+/-533; P<0.001 vs. SVT and vs. PVSal) even more substantially. Kupffer cells from PVT-treated rats were then cultured in the presence of inhibitors of PLA2, COX1, or COX2. When Kupffer cells were treated with mepacrine to inhibit PLA2 (5575+/-453 pg/ml), PGE2 production was not different from that by PVSal-treated controls (6467+/-614 pg/ml), but when Kupffer cells were incubated in the presence of the COX1 inhibitor flurbiprofen (3512+/-407 pg/ml) or the COX2 inhibitor nimesulide (2800+/-830 pg/ml), production was decreased 46.7% and 56.7%, respectively, over control activity without added inhibitor. PVT also increased Kupffer cells COX1 and COX2 mRNA as measured by Northern blot. Heart transplants were then performed from Wistar-Furth donors into Lewis recipients at the time of PVT, SVT, PVSal, or PVT + indomethacin (COX1/2 inhibitor). PVT prolonged allograft survival (12.0+/-0.9 days) compared with PVSal (6.3+/-0.3; P<0.01) or SVT (6.3+/-0.3; P<0.04). Indomethacin shortened graft survival when given with PVT (6.5+/-0.3 days). In summary, PVT increased Kupffer cell PGE2 production, up-regulated transcription of Kupffer cells COX1 and COX2 mRNA, and prolonged cardiac allograft survival. COX1/2 inhibition abrogated the effect of PVT. The results indicated that the immunosuppressive effect of PVT may be mediated by up-regulation of Kupffer cell COX1 and COX2. Manipulation of Kupffer cell arachidonic acid metabolism may be useful in augmentation of PVT-induced immunosuppression.
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PMID:Portal venous transfusion up-regulates Kupffer cell cyclooxygenase activity: a mechanism of immunosuppression in organ transplantation. 923 13

Previously, the spin trapping agent phenyl-N-tert-butylnitrone (PBN) has been shown to decrease the level of nitric oxide synthase mRNA in vivo. This inhibition is suggested to be an underlying mechanism for PBN's wide variety of pharmacological actions in animal models. However, the determination of PBN's cellular pharmacological activities has not been carried out, but is necessary for the understanding of the effects in vivo. Since the known pharmacological effects of PBN are primarily anti-inflammatory in nature, in this study we determined the inhibitory activities of PBN against two inflammatory factors: inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX2). We show here that PBN decreases steady state COX2 mRNA level and COX2 catalytic activity in macrophage cell culture at supra-pharmacological concentrations. While PBN decreases iNOS mRNA, it does not inhibit iNOS catalytic activity, which is consistent with previous in vivo studies. We also studied nuclear factor kappaB (NF-kappaB), a transcription factor that can rapidly activate the expression of genes involved in inflammatory, immune and acute phase responses. The binding of NF-kappaB to iNOS gene has been shown to be critical for iNOS gene expression, and the promoter region of COX2 gene contains NF-kappaB consensus sequence. We show that PBN inhibits lipopolysaccharide-mediated increase of NF-kappaB DNA binding activity with a lower concentration than that for the non-steroidal anti-inflammatory drug (NSAID), salicylate. Furthermore, we show that PBN inhibits COX2 catalytic activity, suggesting that PBN has an NSAID-like function.
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PMID:Inhibition of NF-kappaB, iNOS mRNA, COX2 mRNA, and COX catalytic activity by phenyl-N-tert-butylnitrone (PBN). 982 73

The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP. 1086 45

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) reduce food intake in rodents. Cyclooxygenase (COX) inhibitors have long been known to attenuate these responses, but recent work has revealed the existence of two distinct isoforms of the enzyme, COX1 and COX2, with different characteristics and functions. Therefore, we reassessed the COX involvement using inhibitors with different selectivities for COX1 and COX2. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-minute period, as well as daily food pellet intake. LPS and IL-1beta consistently reduced milk intake. Treatment of the mice with the selective COX1 inhibitor, piroxicam, attenuated the hypophagic responses to IL-1 and LPS. Similar results were obtained with diclofenac. The hypophagic responses to LPS and IL-1beta were not affected by the COX2-selective inhibitors nimesulide and NS-398 at doses considered selective for COX2, but were inhibited by higher doses. Pretreatment of the mice with aspirin, an irreversible inhibitor of COX1 and COX2, prevented the hypophagic response to IL-1, 16 h, but not 40 h later. Taken together, these results suggest that COX1 may be the major isozyme involved in the hypophagic responses to LPS and IL-1, but a role for COX2 cannot be excluded. We also studied the combination of a COX inhibitor with the IL-1 receptor antagonist protein. Consistent with earlier results, both the IL-1 receptor antagonist (IL-1ra) and indomethacin attenuated the hypophagic responses to LPS. Combination of the two treatments produced additive results almost completely preventing the hypophagic response. Because indomethacin almost completely prevented the hypophagic response to IL-1, this additivity suggests that there are multiple mechanisms by which LPS induces hypophagia.
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PMID:The role of cyclooxygenases in endotoxin- and interleukin-1-induced hypophagia. 1097 Jun 76

The etiology of Parkinson's disease is not known. Nevertheless, a significant body of biochemical data from human brain autopsy studies and from animal models points to an ongoing process of oxidative stress in the substantia nigra, which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Oxidative stress, as induced by the neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), has been used in animal models to investigate the process of neurodegeneration to facilitate the development of antioxidant, neuroprotective drugs. It is apparent in these animal models that radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists provide neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided evidence of an inflammatory process. This expresses itself as proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors and neurotrophic factor (NF), kappa-beta and elevation of cytotoxic cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. Both radical scavengers and iron chelators prevent lipopolysaccharide (LPS) and iron-induced activation of NF kappa-beta. If an inflammatory response is involved in Parkinson's disease, it would be logical to consider antioxidants and the newly developed, non-steroidal, anti-inflammatory drugs such as cyclo-oxygenase (COX2) inhibitors as a form of treatment. However, to date there has been little or no success in the clinical treatment of neurodegenerative diseases (for example, Parkinson's disease, ischaemia etc.) where neurons die, while in animal models the same drugs provide neuroprotection. This may indicate that either the animal models employed do not reflect the events in neurodegenerative diseases, or that because neuronal death involves a cascade of events, a single neuroprotective drug is not effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:MPTP and 6-hydroxydopamine-induced neurodegeneration as models for Parkinson's disease: neuroprotective strategies. 1099 72

Monocytes play a pivotal role in various human infectious and inflammatory diseases. To reveal a whole picture of pathophysiologic function of activated human monocytes, this study used the serial analysis of gene expression (SAGE) procedure in lipopolysaccharide (LPS)-stimulated human monocytes. A total of 35 874 tags corresponding to more than 12 000 different transcripts were sequenced. Comparison of gene expression profile with that of resting monocytes revealed the LPS-inducible gene expression profile. Many cytokines and chemokines, including interleukin (IL)-6, IL-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, MIP-2beta, MIP-2alpha, liver and activation-regulated chemokine (LARC), MIP-1alpha, thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), growth-regulated oncogene (GRO) alpha, and IL-8, were observed in the highest inducible transcripts. Other genes encoding plasminogen activator inhibitor type 2 (PAI-2), Hc-gp39, apolipoproteins, malate dehydrogenase, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase (COX2) were also highly elevated in LPS-stimulated monocytes. Moreover, up-regulation of Naf1beta, IL-7 receptor, adenosine receptor A2a, and many novel genes was newly identified. These results suggest that the LPS-inducible gene products may be involved in cell activation and migration, angiogenesis, tissue remodeling, and metabolism, and thus may orchestrate the inflammatory reactions. On the other hand, the expression of numerous sets of novel genes was discovered to be down-regulated on LPS stimulation. This study represents the first comprehensive analysis of LPS-inducible gene expression in human monocytes and provides tremendous novel information for the function of LPS-activated monocytes and targets for diagnosing, monitoring, and treating sepsis and various human infectious and inflammatory diseases.
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PMID:Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. 1100 15

Interleukin-1 (IL-1) induces hypophagia, which can be reduced by cyclooxygenase (COX) inhibitors. Earlier studies with COX knockout (COXko) mice suggested that COX2 was more important for hypophagia than COX1. However, behavioral responses occur long before COX2 is induced. Hypophagia was assessed in mice by measuring the intake of sweetened milk in a brief period. The intake was reduced within 30 min after intraperitoneal injection of IL-1beta and was depressed for about 2 h. When milk intake was measured 30 to 40 min after IL-1beta, COX1ko mice showed an attenuated response, whereas COX2ko mice responded more like wild-type animals. By contrast, 90 to 120 min after IL-1beta COX1ko mice responded normally, whereas COX2ko mice showed only small responses. The COX2-selective inhibitor, celecoxib, failed to alter the response to IL-1beta 30 min after administration, but low doses antagonized the effects of IL-1beta at 90 to 120 min. The COX1-selective inhibitor, SC560, attenuated both the early and late responses, but a larger effect at 30 min than at 90 min suggested a role for COX1 at the earlier time. These results suggest that shortly after IL-1beta administration, COX1 is the major enzyme involved in the reduction of milk intake, whereas at later times COX2 is more important, paralleling its induction. Celecoxib also attenuated the milk intake response observed 2 h after lipopolysaccharide (LPS), and the reductions of food pellet intake and body weight induced by IL-1beta and LPS in the subsequent 24 h, suggesting that the role of COX2 may be more significant biologically than that of COX1.
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PMID:Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. 1218 60

Unlike the tocopherols, the tocotrienols, also members of the vitamin E family, have an unsaturated isoprenoid side chain. In contrast to extensive studies on tocopherol, very little is known about tocotrienol. Because the nuclear factor-kappaB (NF-kappaB) pathway has a central role in tumorigenesis, we investigated the effect of gamma-tocotrienol on the NF-kappaB pathway. Although gamma-tocotrienol completely abolished tumor necrosis factor alpha (TNF)-induced NF-kappaB activation, a similar dose of gamma-tocopherol had no effect. Besides TNF, gamma-tocotrienol also abolished NF-kappaB activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1beta, and epidermal growth factor. Constitutive NF-kappaB activation expressed by certain tumor cells was also abrogated by gamma-tocotrienol. Reducing agent had no effect on the gamma-tocotrienol-induced down-regulation of NF-kappaB. Mevalonate reversed the NF-kappaB inhibitory effect of gamma-tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. Gamma-tocotrienol blocked TNF-induced phosphorylation and degradation of IkappaBalpha through the inhibition of IkappaBalpha kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. gamma-Tocotrienol also suppressed NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IkappaBalpha kinase but not that activated by p65. Additionally, the expressions of NF-kappaB-regulated gene products associated with antiapoptosis (IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, XIAP, Bfl-1/A1, TRAF1, and Survivin), proliferation (cyclin D1, COX2, and c-Myc), invasion (MMP-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor) were down-regulated by gamma-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that gamma-tocotrienol inhibited the NF-kappaB activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.
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PMID:Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. 1711 79


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