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)

Interleukin (IL)-12, interferon (IFN)-gamma, and other inflammatory cytokines play an important role in the pathogenesis of autoimmune insulitis and diabetes in NOD mice, and inhibition of these cytokines is likely to be beneficial. In this study, we found that Pentoxifylline (PTX) and Rolipram (phosphodiesterase [PDE] inhibitors that induce increased intracellular cAMP) can block inflammatory cytokine production. Inhibition of IL-12 and IFN-gamma secretion was demonstrated in macrophages activated with lipopolysaccharide or T-cells stimulated through the CD3/T-cell receptor complex, respectively. Moreover, strong inhibition of IL-12 was demonstrated in vivo in superantigen-immunized mice. Rolipram was inhibitory at concentrations as low as 10(-8) to 10(-7) mol/l, and on a molar basis, it was 100-fold more effective than PTX. Tumor necrosis factor-alpha was also inhibited, but IL-4 was less sensitive to suppression. In NOD mice, both PTX and Rolipram reduced the severity of insulitis and prevented diabetes, with or without cyclophosphamide administration (which precipitates onset of disease). This protection of NOD mice was still apparent over 10 weeks after withdrawal of the drug treatment. It appears that blocking the activity of type IV PDE is sufficient to mediate the effects reported in this study, since Rolipram inhibits only this isoform, unlike PTX (a general inhibitor). PTX and Rolipram may be effective in the treatment of autoimmune diabetes or other conditions characterized by excessive production of inflammatory cytokines.
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PMID:The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice. 956 89

The type 4 phosphodiesterase (PDE4) is the predominant PDE isozyme in various leukocytes and plays a key role in the regulation of inflammatory cell activation. There are four PDE4 subtypes (A, B, C, and D), and within each subtype, there are multiple variants. Very recently, we found in monocytes that PDE4B gene expression is selectively induced by lipopolysaccharide (LPS) and that the induction is inhibited by interleukin (IL)-10 and IL-4. In this study, we show that the PDE4B gene is constitutively expressed in neutrophils and that this expression remains unaffected by LPS or IL-10. PDE4B is the predominant subtype in neutrophils and in unstimulated or LPS-stimulated monocytes, and in these cells, the PDE4B2 variant is the only detectable molecular species of PDE4B. Therefore, PDE4B2 is the predominant PDE isoform in human neutrophils and monocytes, and its expression is regulated differently by these two cell types. Furthermore, leukocytes are the most dominant source of PDE4B2, suggesting that PDE4B2 is a relatively specific target for discovering anti-inflammatory drugs.
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PMID:Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. 1038 98

During differentiation of human monocytes (CD14(+)/CD1a(-)) to CD14(-)/CD1a(+)dendritic cells (DC), a drastic decrease in PDE4 activity was observed, while activities of PDE1 and PDE3 substantially increased. DC released tumour necrosis factor-alpha (TNF) in response to lipopolysaccharide (LPS) challenge, which was abolished both by dexamethasone and the cyclic AMP-elevating drugs db-cAMP and PGE(2). In addition, rolipram, at PDE4-selective concentrations, blocked TNF release by 37 +/- 5% (P<0.05 vs. control). The PDE3 inhibitor motapizone only marginally influenced TNF synthesis, but a synergistic inhibitory effect was noted in combination with rolipram. Qualitatively, similar inhibitory effects were observed in DC-stimulated T cell responses. Motapizone, lacking efficacy when used alone, increased the effect of rolipram in blocking CD4(+)T lymphocyte proliferation in response to antigen (Ag) (tetanus toxoid, TT; keyhole limpet hemocyanin, KLH) presented by DC and in allogeneic mixed leukocyte reactions (MLR). However, in these coculture systems the T cells rather than the DC seem to be the major target cells of PDE-inhibitor action. In summary, PDE inhibitors can affect DC function directly as demonstrated by blocking TNF release and their efficacy reflects the changes in the PDE activity profile during differentiation from their monocyte precursors. These results together with the known efficacy of PDE3/4 inhibitors in T cells support the concept of combined PDE3/4 inhibitors for asthma therapy.
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PMID:Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated human dendritic cells (DC) and the influence of PDE inhibitors on DC function. 1058 79

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC(50) of 2.2 nM. IC(50) values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED(30) values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.
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PMID:A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity. 1099 87

We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED(50)=15.8 mg kg(-1)) plasma levels of TNF-alpha in rats challenged with LPS (1.5 mg kg(-1), i.p.). Aerosolized LPS induced a peak in TNF-alpha levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL-1beta levels and the initial plateau of neutrophilia observed in the BAL fluid. SB 203580 (100 mg kg(-1)), had no effect on peak TNF-alpha levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg(-1)) significantly reduced both TNF-alpha levels and neutrophilic inflammation. However, the BAL fluid from rats pre-treated with either compound significantly inhibited TNF-alpha release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively). Alternatively, SB 203580 (100 mg kg(-1)) produced dose-related inhibition of BAL IL-1beta levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4 h after LPS challenge. P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment. P38 kinase appears to be involved in the release of IL-1beta and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology.
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PMID:Role of p38 MAP kinase in LPS-induced airway inflammation in the rat. 1130 43

Ginsenosides are the major principles of Panax ginseng C. A. Meyer (Araliaceae) used as a mild oriental folk medicine. In this report, we have examined the inhibitory potency of protopanaxadiol ginsenosides (PPDGs) such as Rb1, Rb2 and Rc, and their co-treatment effect with known tumor necrosis factor (TNF)-alpha antagonists on TNF-alpha production in either murine (RAW264.7) or human (U937) macrophages stimulated with lipopolysaccharide (LPS). Rb1, and Rb2 strongly suppressed TNF-alpha production in RAW264.7 cells with an IC50 of 56.5 and 27.5 microM, respectively, and in differentiated U937 cells with an IC50 of 51.3, and 26.8 microM, respectively. The inhibitory activity of Rb1 and Rb2 was significantly increased by pharmacological agents against protein kinase C, protein tyrosine kinase, and protein kinase A, and anti-rheumatoid arthritis drugs, such as chloroquine and steroid drugs. In contrast, only cyclic AMP phosphodiesterase (cAMP PDE) inhibitors among cAMP-elevating agents did not change the inhibitory potency of PPDGs. These data suggest that PPDGs may possess potential therapeutic efficacy against TNF-alpha mediated disease and the therapeutic potency of PPDGs may be enhanced when co-treated with various kinds of known TNF-alpha antagonists but not with cAMP PDE inhibitors.
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PMID:In vitro inhibitory effect of protopanaxadiol ginsenosides on tumor necrosis factor (TNF)-alpha production and its modulation by known TNF-alpha antagonists. 1134 90

We investigated the effects of inhibitors of cAMP-specific phosphodiesterase type IV (PDE IV) on cultured rat microglial cells. Microglial cells expressed mRNA encoding PDE IV. Rolipram and RO-20-1724, specific inhibitors of PDE IV, elevated the intracellular cAMP level much higher than the other types of PDE inhibitors. cAMP in astrocytes but not in cerebrocortical neurons was similarly increased in response to treatment with PDE IV inhibitors examined. The PDE IV inhibitors, a beta-adrenergic agonist isoproterenol and an adenylyl cyclase stimulant forskolin suppressed the proliferation of microglial cells as revealed by PCNA-immunocytochemical staining. The PDE IV inhibitors suppressed release of TNF alpha and nitric oxide (NO) from lipopolysaccharide-activated microglial cells in pure culture, while they did not affect NO release from microglial cells in neuron-microglia coculture. The PDE IV inhibitors also suppressed superoxide anion production by phorbol ester-treated microglial cells. Isoproterenol and forskolin similarly suppressed the macrophage-like functions of activated microglial cells. However, the PDE IV inhibitors displayed novel effects distinct from those of isoproterenol, forskolin and 8Br-cAMP, regarding expression of mRNAs encoding PDE IV, metallothionein-1 and hemeoxigenase-1. The present data showed that the PDE IV inhibitors can be available to control microglial function and that their effects on glial cells should be taken into account when PDE IV inhibitors are used for treatment of brain diseases, such as multiple sclerosis.
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PMID:Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents. 1180 23

The aim of this study was to investigate the role of the inhibitors of different PDE isoenzymes (PDE 1-5) on the production of two pro-inflammatory cytokines - tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Two in vitro models were used to compare the antiinflammatory properties of PDE inhibitors with that of glucocorticoids. The effect on TNF release from diluted human blood following lipopolysaccharide (LPS from Salmonella abortus equi) stimulation as well as the GM-CSF and TNF release from human nasal polyp cells following allergic stimulation were investigated. Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities. In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors. Amrinone and milrinone, selective PDE3 inhibitors, suppressed TNF secretion to a lesser extent. The effects of theophylline (unspecific PDE inhibitor), vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor) and the PDE5 inhibitors zaprinast and E 4021 were weak. In human blood, the tested glucocorticoids beclomethasone, dexamethasone and fluticasone inhibited the LPS induced TNF release potently in a concentration dependent manner, whereas in dispersed human nasal polyp cells, the effect of the glucocorticoids on allergically induced TNF release, with the exception of dexamethasone, was much less pronounced. Glucocorticoids were the most potent inhibitors of GM-CSF release and the effect correlates well with the affinity to the glucocorticoid receptor. The selective PDE 4 inhibitors, and to a certain extent the PDE3 inhibitors amrinone and milrinone, reduced the GM-CSF release in a concentration dependent manner. In all investigations selective PDE4 inhibitors reduced TNF release to a much higher degree (4-10 fold) than GM-CSF release.
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PMID:Modulation of TNF and GM-CSF release from dispersed human nasal polyp cells and human whole blood by inhibitors of different PDE isoenzymes and glucocorticoids. 1196 59

Damage to the white matter in the brain during development can lead to cerebral palsy (CP), a heterogeneous group of clinical syndromes that results in life-long disorders of movement and posture. Periventricular leukomalacia (PVL) is a pathological process within the white matter characterized by oligodendrocyte loss and is associated with the development of CP. Clinically, CP and PVL are associated with intrauterine infection and inflammation, but mechanisms involved are not well understood. We developed a model of intrauterine inflammation in Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on developing glia. Pregnant rats were intracervically injected with lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that caused low fetal mortality was determined. At E20, treated fetuses had increased TUNEL(+) nuclei and tumor necrosis factor (TNF)-alpha-immunoreactive areas within the brains. In a second series of animals allowed to survive until postnatal day 21 (PND 21), immunostaining was performed against several glial markers. Staining for the oligodendrocyte-specific proteins 2', 3'-cyclic nucleotide phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in treated pups compared to shams within the corpus callosum, a white matter structure used as a representative area of developing white matter. Treated pups had activated astrocytes lining cerebral blood vessels, as observed by glial fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated microglia were not detected using OX42 as a cell marker. Our model of intrauterine inflammation causes increased TUNEL and TNF-alpha staining early after injury, suggesting increased apoptotic cell death, possibly by cytokine-related mechanisms.
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PMID:Effects of intrauterine inflammation on developing rat brain. 1240 11

V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic.
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PMID:Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. 1267 Jul 78


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