UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. It has been proposed that in inflammatory conditions, in which both the inducible isoforms of nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) are induced, inhibition of NOS also results in inhibition of arachidonic acid metabolism. In the present study we have investigated whether mercaptoalkylguanidines, a novel class of selective iNOS inhibitors, may also influence the activity of cyclo-oxygenase (COX). Therefore, the effect of mercaptoethylguanidine (MEG) and related compounds on the activity of the constitutive (COX-1) and the inducible COX (COX-2) was investigated in cells and in purified enzymes. Aminoguanidine, NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine methyl ester (L-NAME) were also studied for comparative purposes. 2. Western blot analysis demonstrated a significant COX-1 activity in unstimulated J774 macrophages and in unstimulated human umbilical vein endothelial cells (HUVEC). Immunostimulation of the J774 macrophages by endotoxin (lipopolysaccharide of E. coli, LPS 10 micrograms ml-1) and interferon gamma (IFN gamma, 100 u ml-1) for 6 h resulted in a significant induction of COX-2, and a down-regulation of COX-1. No COX-2 immunoreactivity was detected in unstimulated HUVEC or unstimulated J774 cells. Therefore, in subsequent studies, the effect of mercaptoalkylguanidines on COX-1 activity was studied in HUVEC stimulated with arachidonic acid for 6 h, and in J774 cells stimulated with arachidonic acid for 30 min. The effect of mercaptoalkylguanidines on COX-2 activity was studied in immunostimulated J774 macrophages, both on prostaglandin production by endogenous sources, and on prostaglandin production in response to exogenous arachidonic acid stimulation. In addition, the effect of mercaptoalkylguanidines on purified COX-1 and COX-2 activities was also studied. 3. In experiments designed to measure COX-1 activity in HUVEC, the cells were stimulated by arachidonic acid (15 microM) for 6 h. This treatment induced a significant production of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable metabolite of prostacyclin), while nitrite production was undetectable by the Griess reaction. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of 6-keto-PGF1 alpha, with an IC50 of 20 microM. However, aminoguanidine, L-NAME or L-NMA (up to 3 mM) did not affect the production of 6-keto-PGF1 alpha in this experimental system. In experiments designed to measure COX-1 activity in J774.2 macrophages, the cells were stimulated by arachidonic acid (15 microM) for 30 min; this also induced a significant production of 6-keto-PGF1 alpha and MEG (1 microM to 3 mM), aminoguanidine (at 1 and 3 mM), but neither L-NAME nor L-NMA inhibited the production of prostaglandins. 4. In experiments designed to measure prostaglandin production by COX-2 with endogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h in the absence or presence of various inhibitors. In experiments designed to measure prostaglandin production by COX-2 with exogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h, followed by a replacement of the culture medium with fresh medium containing arachidonic acid and various inhibitors. Both of these treatments induced a significant production of 6-keto-PGF1 alpha. Nitrite production, an indicator of NOS activity, was moderately increased after immunostimulation. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of COX metabolites. Similar inhibition of LPS-stimulated 6-keto PGF1 alpha production was shown by other mercaptoalkylguanidines (such as N-methyl-mercaptoethylguanidine, N,N'-dimethyl-mercaptoethylguanidine, S-methyl-mercaptoethylguanidine and guanidino-ethyldisulphide), with IC50 values ranging between 34-55 microM. However, aminoguanidine, L-NAME and L-NMA (up to 3 mM) did not affect the production of prostaglandins.5. In comparative experiments indomethacin, a non selective COX inhibitor, and NS-398, a selective COX-2 inhibitor, reduced (LPS) stimulated 6-keto-PGF1alpha production in J774 macrophages in a dose-dependent manner without affecting nitrite release. Indomethacin, but not NS-398, inhibited 6-keto-PGF1alpha production in the HUVECs. 6.The inhibitory effect of MEG was due to direct inhibition of the catalytic activity of COX as indicated in experiments with purified COX-1 and COX-2. MEG dose-dependently inhibited the purified COX-1 and COX-2 activity with IC50 values of 33microM and 36microM, respectively. Aminoguanidine (at the highest concentrations) inhibited the formation of COX-1 metabolites, without affecting COX-2 activity. High doses of L-NAME (3mM) decreased COX-1 activity only, while L-NMA (up to 3mM) had no effect on the activity of either enzyme. 7.These results suggest that MEG and related compounds are direct inhibitors of the constitutive and the inducible cyclo-oxygenases, in addition to their effects on the inducible NOS. The additional effect of mercaptoalkylguanidines on COX activity may contribute to the beneficial effects of these agents in inflammatory conditions where both iNOS and COX-2 are expressed.
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PMID:The inhibitory effects of mercaptoalkylguanidines on cyclo-oxygenase activity. 903 36

In a mouse macrophage-like cell line, RAW264.7, arachidonic acid was cleaved within 30 min of lipopolysaccharide (LPS)-treatment. However, prostaglandin (PG) synthesis did not accompany this cleavage, being delayed by 4 h, although significant PGH synthase (PGHS) activity was detected in the lysate of LPS-nontreated cells. The K(m) value of this basal PGHS activity toward arachidonic acid was more than one hundred-fold higher than that for the lysate of cells treated with LPS for 4 h. Changes in the sensitivity of the PGHS activity to nonsteroidal antinflammatory drugs after LPS-treatment also suggested induction of PGHS with different properties from that in the case of basal PGHS. The concomitant increase in PGH synthase (PGHS) activity with the induction of PGHS-2 protein after LPS-treatment suggested a contribution by PGHS-2 to the delayed synthesis of PGs in LPS-treated macrophage cells. As for PGHS in the control cells without LPS-treatment, a different K(m) value from that of PGHS-1 and the lack of cross-reactivity to anti-PGHS-1 antibodies suggested that this basal PGHS was different from the typical PGHS-1. The lower affinity of this enzyme for arachidonic acid might be the reason for the failure to release PGs by the cells without LPS-treatment.
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PMID:Delayed release of prostaglandins from arachidonic acid and kinetic changes in prostaglandin H synthase activity on the induction of prostaglandin H synthase-2 after lipopolysaccharide-treatment of RAW264.7 macrophage-like cells. 914 2

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac > indomethacin approximately naproxen > nimesulide approximately meloxicam approximately piroxicam > NS-398 approximately SC-57666 > SC-58125 > CGP 28238 approximately etodolac > L-745,337 > DFU. 7. DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg-1 vs 2.0 mg kg-1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg-1 vs 1.5 mg kg-1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50 = 0.76 mg kg-1 vs 1.1 mg kg-1 for indomethacin). 8. In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg-1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg-1), meloxicam (3 mg kg-1) or etodolac (10-30 mg kg-1). A 5 day administration of DFU in squirrel monkeys (100 mg kg-1) did not affect chromium leakage in contrast to diclofenac (1 mg kg-1) or naproxen (5 mg kg-1). 9. The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX-1 activity are not important in acute inflammatory responses and that a high therapeutic index of anti-inflammatory effect to gastropathy can be achieved with a selective COX-2 inhibitor.
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PMID:Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. 914 94

1. Within vessels, the formation of nitric oxide (NO) or prostaglandins is normally catalysed in the endothelium by constitutive isoforms of NO synthase (eNOS) and cyclo-oxygenase (COX-1), respectively. However, during inflammatory conditions, the underlying smooth muscle acquires the ability to release NO and prostaglandins after the expression of inducible isoforms of NOS (iNOS) and COX (COX-2). The co-induction of iNOS and COX-2 has been studied over 24 h in isolated vascular smooth muscle cells in vitro. However, due to the limitation of using cultured cells, the relationship between the activities of iNOS and COX over longer periods has not been addressed. Moreover, the relative contribution of the endothelium to the production of NO and prostaglandins under inflammatory conditions is not completely understood. 2. Here using an organ culture system, we have determined the profile of COX (6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), PGE2, thromboxane B2 (TXB2) and NOS (nitrite and nitrate) metabolites released over a period of 10 days from segments of rat aorta. In each case, segments from the same animal were left untreated or treated with bacterial lipopolysaccharide (LPS; 10 micrograms ml-1) in order to induce iNOS and COX-2. Prostaglandins were measured by radioimmunoassay whilst nitrite and nitrate were measured, respectively, by Greiss reaction alone, or following a nitrate reductase step. The isoforms of NOS and COX responsible for metabolite release were characterized pharmacologically by use of inhibitors and at the molecular level by reverse transcription polymerase chain reaction with specific primers for iNOS, eNOS, COX-1 and COX-2. In separate experiments the role of the endothelium in the release of nitrite, nitrate and prostaglandins and in the expression of iNOS, eNOS, COX-1 and COX-2 was determined by comparing responses in endothelium denuded and endothelium-intact segments of rat aorta. 3. Under control culture conditions vessels released prostaglandins in the following rank order 6-keto PGF1 alpha = PGE2 > > TXB2. LPS increased the release of 6-keto PGF1 alpha and PGE2 but not of TXB2, an effect that was inhibited by the protein synthesis inhibitor cycloheximide (1 microM), the anti-inflammatory steroid dexamethason (1 microM), the nonsteroidal anti-inflammatory drug indomethacin (30 microM) and, where tested, the selective COX-2 inhibitor NS-398 (30 microM). Similarly, segments of rat aorta released detectable levels of nitrite and nitrate, which were reduced by NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), which inhibits all isoforms of NOS, and by dexamethasone (1 microM), which inhibits the induction of iNOS. The proportion of nitrate to nitrite released over the 10 day period varied greatly from approximately 1:1 on days 5 to 8 to 5:1 on day 9. However, the sum of nitrite and nitrate (NOx) as well as PGE2 remained elevated over the whole 10 day period. The formation of 6-keto PGF1 alpha peaked on days 1 and 2. 4. In freshly prepared tissue, mRNAs for eNOS, COX-1, iNOS and COX-2 were detected. After 24 h in culture, there was an apparent increase in the level of mRNAs for iNOS and COX-2 but not for eNOS or COX-1, an effect that was further enhanced when LPS was included in the culture medium. The expressions of mRNA for eNOS, COX-1, iNOS or COX-2 were not greatly different in vessels with intact or disrupted endothelium. Similarly the release of NOx or PGE2 by vessels after the 1st or 9th day in culture were not significantly different from vessels prepared with or without endothelium. 5. Thus, COX-2 and iNOS are co-induced in intact vessels in culture, with the vascular smooth muscle being the main site of mediator generation. In contrast to data from isolated cells in culture (observed usually over 1 day), both COX and NOS activities in cultured blood vessels were elevated for at least 10 days. Also, unlike isolated cells in culture, the COX and NOS pathways were active independently; L-NAME had little effect on the activity of COX and indomethacin had little effect on the activity of NOS.
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PMID:Characterization of the induction of nitric oxide synthase and cyclo-oxygenase in rat aorta in organ culture. 914 96

The relative anti-inflammatory activities of the immunomodulators HR325 and leflunomide, or its active metabolite A77 1726, were examined by determining potencies in vitro on prostaglandin endoperoxide H synthase (PGHS) and in vivo in rat air pouch inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) were used as comparators. HR325 was more potent than A77 1726 as an inhibitor of PGHS in guinea pig polymorphonuclear leukocytes (IC50 = 415 and 4400 nM, respectively) and on isolated ovine PGHS-1 (IC50 = 64 and 742 microM) and PGHS-2 (IC50 = 100 and 2766 microM). In vivo, in rat carrageenan air pouch inflammation, HR325 but not leflunomide at 25 mg/kg inhibited accumulation of leukocytes (48%) and PGE2 (61%). HR325 was also more potent than A77 1726 against human peripheral blood mononuclear cell PGHS-1 [IC50 = 1.6 and 25.6 microM (thromboxane B2 production) or 1.1 and 8 microM (PGE2 production)] and lipopolysaccharide-induced PGHS-2 in human adherent peripheral blood mononuclear cells (IC50 = 435 nM and 9.5 microM) and peripheral blood polymorphonuclear leukocytes (IC50 = 91 nM and 3.2 microM). HR325 had low PGHS-2 selectivity in the human (2.5-12-fold) and was a more potent PGHS-2 inhibitor than naproxen, ibuprofen and piroxicam (28-fold). Assays using endogenous arachidonic acid as substrate yielded IC50 values for NSAIDs that were in general markedly lower than those published for assays using 10 microM substrate. With this approach, piroxicam had reasonable activity on human PGHS-2 (IC50 = 260-290 nM). Only NS398 and flufenamic acid were PGHS-2 selective in the human (90-330-fold and 37-60-fold, respectively); the other NSAIDs were either PGHS-1-selective (naproxen, ibuprofen, flurbiprofen and indomethacin) or nonselective (piroxicam and diclofenac). Inclusion of 10% human plasma reduced HR325 potency against PGHS-1 in human peripheral blood mononuclear cells approximately 32-fold (IC50 = 36 microM). Plasma protein binding further reduced HR325 potency (IC50 = 164 microM) and minimized the difference between HR325 and A77 1726 (IC50 = 292 microM) in a whole blood PGHS assay. Whether the greater activity against human PGHS-2 would allow HR325 to exhibit NSAID-like therapeutic effects in humans remains unclear.
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PMID:Potencies of leflunomide and HR325 as inhibitors of prostaglandin endoperoxide H synthase-1 and -2: comparison with nonsteroidal anti-inflammatory drugs. 922 72

NSAIDs inhibit the conversion of arachidonic acid into Prostaglandin G2 and Prostaglandin H2 which is catalyzed by the enzyme cyclooxygenase (COX). Two genetically distinct isoforms have been discovered, COX-1 and COX-2. While COX-1 is thought to account for homeostatic amounts of eicosanoids, COX-2 is induced during inflammation leading to pathologic amounts of eicosanoids. Since NSAIDs inhibit both COX isoforms, antiinflammatory drug research has refocused to discovering COX-2 inhibitors that do not inhibit COX-1. For this purpose, we have developed a whole cell assay system using the human erythroleukemic cell line HEL as a source for COX-1 and the human monocytic cell line Mono Mac 6 as a source for COX-2. Mono Mac 6 cells express high amounts of COX-2 upon stimulation with lipopolysaccharide (LPS) in the absence of any detectable COX-1 protein. On the other hand, we find HEL cells to naturally express COX-1 protein, but not COX-2. Testing of a panel of NSAIDs as well as some COX-2 specific inhibitors showed that this assay system is suitable for identifying compounds that selectively inhibit either COX-1 or COX-2. This test system offers the advantage of assessing COX-1 and COX-2 inhibitors within the human species, within a similar test set-up, and circumvents the need for tedious purification of either platelets or peripheral blood monocytes.
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PMID:Isoenzyme-specific cyclooxygenase inhibitors: a whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6. 927 72

Treatment with ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) has been reported to decrease the incidence as well as slow down the progression of Alzheimer's disease. Understanding the mechanism of this therapeutic effect would provide a target for development of drugs which may be devoid of side effects observed with NSAIDs. In addition to inhibiting cyclooxygenase (COX), the NSAIDs have recently been shown to decrease inducible nitric oxide synthase (iNOS) activity. Ibuprofen and other NSAIDs had no direct effect on catalytic activity of iNOS, but decreased levels of iNOS mRNA. The mechanism of action of ibuprofen on reduction of iNOS activity has been further investigated in the present study using rat primary cerebellar glial cell cultures. In addition, the effect of ibuprofen on COX mRNA expression and prostaglandin formation was also studied. Glial cells treated with E. coli lipopolysaccharide (LPS) and interferony (INFgamma) for 16 h expressed iNOS and COX. Ibuprofen did not directly inhibit iNOS activity. However, when ibuprofen was incubated at the same time with LPS and INFgamma for 16 h, enzyme activity was reduced, with an IC50 of 0.76 mM. Ibuprofen concentration-dependently decreased iNOS mRNA levels, with an IC50 > 2 mM. Thus, there was no correlation between decrease in iNOS activity and reduction in iNOS mRNA levels. Ibuprofen decreased iNOS protein levels, as determined by Western blot, with an IC50 of 0.89 mM. The data suggest that the reduction in iNOS activity by ibuprofen is due to inhibition of post-transcriptional processing of this enzyme. Ibuprofen had no effect on constitutive COX (COX-1) or inducible COX (COX-2) mRNA expression. However, ibuprofen inhibited PGE2 formation with an IC50 of 0.86 mM. The anti-inflammatory actions of ibuprofen have been related to inhibition of COX and, subsequently, reducing prostaglandin formation. Since the potency of ibuprofen for inhibition of PGE2 formation and reduction in iNOS activity are similar, it is suggested that, at therapeutically effective doses, a decrease in iNOS activity may also occur in vivo. Therefore, reduction in iNOS protein levels in the brain may have a role in preserving the integrity of neurons in individuals susceptible to Alzheimer's disease.
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PMID:Ibuprofen: effect on inducible nitric oxide synthase. 940 24

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

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