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)

delta 9-Tetrahydrocannabinol (delta 9-THC) a prototypic compound belonging to the family of agents known as cannabinoids, produces a wide variety of biological effects, including inhibition of immune function. The putative mechanism for cannabinoid biological action involves binding to cannabinoid receptor types 1 and 2 (CB1 and CB2) to negatively regulate adenylate cyclase and inhibit intracellular signaling via the cAMP cascade. In the current study, we show that delta 9-THC produces a marked inhibition of inducible nitric oxide synthase (iNOS) transcription and nitric oxide production by the macrophage line RAW 264.7 in response to lipopolysaccharide (LPS). Analysis of RAW 264.7 cell RNA demonstrated transcripts for CB2 but not CB1. Treatment of RAW 264.7 with delta 9-THC inhibited forskolin-stimulated cAMP production in a dose-related manner, verifying the expression of functional cannabinoid receptors by this cell line. iNOS transcription, which is regulated in part by the nuclear factor-kappa B/Rel (NF-kappa B/Rel) family of transcription factors, has been shown to be under the control of the cAMP signaling cascade. We demonstrate that delta 9-THC inhibits the activation and binding of NF-kappa B/Rel proteins to their cognate DNA site, kappa B, in response to LPS stimulation. LPS treatment of RAW 264.7 cells also induced the activation of the cAMP cascade, as indicated by an increase in binding of nuclear factors to the cAMP response element. Activation of CRE binding proteins was inhibited by delta 9-THC. Forskolin treatment of RAW 264.7 cells induced both kappa B and cAMP response element binding activity and was likewise inhibited by delta 9-THC. Collectively, this series of experiments indicates that NF-kappa B/Rel is positively regulated by the cAMP cascade to help initiate iNOS gene expression in response to LPS stimulation of macrophages. This activation of iNOS is attenuated by delta 9-THC through the inhibition of cAMP signaling.
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PMID:Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. 870 Jan 41

Nitric oxide produced by inducible nitric-oxide synthase (iNOS) in different brain cells in response to various cytokines plays an important role in the pathophysiology of stroke and other neurodegenerative diseases. This study underlines the importance of cAMP in inhibiting the induction of NO production by lipopolysaccharide (LPS) and cytokines in rat primary astrocytes. Compounds (forskolin, 8-bromo-cAMP, and (Sp)-cAMP) that increase cAMP and activate protein kinase A (PKA) were found to inhibit LPS- and cytokine-mediated production of NO as well as the expression of iNOS, whereas compounds (H-89 and (Rp)-cAMP) that decrease cAMP and PKA activity stimulated the production of NO and the expression of iNOS in rat primary astrocytes. Forskolin, but not the inactive analogue 1,9-dideoxyforskolin, inhibited NO production and iNOS expression in a dose-dependent manner in astrocytes. The inhibition of LPS- and/or cytokine-induced NO production in rat C6 glial cells by forskolin suggest that similar to astrocytes, iNOS expression in C6 cells is also regulated by similar mechanisms. In contrast, in rat peritoneal macrophages the cAMP analogues stimulated the LPS- and cytokine-induced production of NO. In vitro, the PKA had no effect on iNOS activity in LPS-treated astrocytes or macrophages, suggesting that PKA modulates the intracellular signaling events associated with the induction of iNOS biogenesis rather than the post-translational modification of iNOS. The compounds which activate PKA activity, blocked the activation of NF-kappabeta in astrocytes but stimulated the activation of NF-kappabeta in macrophages. This differential regulation of NF-kappabeta activation in two different cell types (astrocytes and macrophages) by the same second messenger (cAMP) indicates that intracellular events or pathways in the activation of NF-kappabeta may be different. Moreover, this inhibition of iNOS expression in LPS- and cytokine-treated astrocytes by cAMP may be of therapeutic potential in NO-mediated cytotoxicity in neurodegenerative diseases.
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PMID:Increasing cAMP attenuates induction of inducible nitric-oxide synthase in rat primary astrocytes. 906 41

Previous studies from our laboratories demonstrated that human decidual macrophages and peripheral mononuclear cells express renin. In the present study, we found that U-937 monocytes, induced to differentiate into macrophage-like cells by treatment with phorbol dibutyrate (PDBU), express renin mRNA and release renin (95%, of which is in the form of prorenin). Treatment of these PDBU-exposed cells with dibutyryl-cAMP (1 mM) caused a 20-fold increase in renin mRNA and a 10-fold increase in prorenin release. Forskolin (10 microM), an activator of adenylyl cyclase, and terbutaline (100 microM), a beta2-adrenergic agonist known to increase cAMP levels, also increased renin mRNA and prorenin release. The secretory response to terbutaline was potentiated by the type IV cyclic AMP-phosphodiesterase (PDE) inhibitor Ro 20-1724 (50 microM). Angiotensin II agonist inhibited the stimulatory effect of terbutaline on renin secretion as did the cytokines tumor necrosis factor-alpha and lipopolysaccharide plus interferon-gamma. Since other studies have shown that U-937 cells possess beta2-adrenergic receptors and express mainly the type IV PDE, the present findings strongly suggest that beta-adrenergic receptors in mononuclear cells are coupled to renin expression via the cAMP transduction pathway. The results support a possible role for the renin-angiotensin system in macrophage function and suggest potential autocrine regulatory mechanisms in prorenin expression.
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PMID:Beta-adrenergic regulation of renin expression in differentiated U-937 monocytic cells. 925 63

Treatment of cultured rat Kupffer cells with lipopolysaccharide (LPS) resulted in a time-dependent increase in the expression of the inducible isoform of nitric-oxide synthase (iNOS). Agents that elevated intracellular cAMP levels (e.g. forskolin, dibutyryl cAMP, cholera toxin, and isoproterenol) markedly decreased nitrite production and iNOS protein formation by LPS-stimulated Kupffer cells. Furthermore, inhibition of LPS-induced nitrite formation and iNOS protein levels by these agents was enhanced in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Forskolin, the most potent inhibitor of LPS-induced nitrite formation by Kupffer cells, decreased iNOS mRNA levels in a time-dependent manner. Time course studies indicated that forskolin was most effective at inhibiting LPS-induced nitrite formation and iNOS mRNA levels by Kupffer cells when added before LPS. Message stability studies established that forskolin did not enhance the rate of decay of LPS-induced iNOS mRNA. Nuclear run-on assays revealed that forskolin decreased LPS-induced transcription of the iNOS gene. Treatment of Kupffer cells with LPS induced the translocation of the p65 subunit of nuclear factor kappaB (NF-kappaB) into the nucleus, and this process was abolished by forskolin. In addition, the LPS-dependent degradation of IkappaBalpha was not observed in forskolin-treated cells; the levels of the p65 subunit of NF-kappaB were minimal in the nucleus at the same time. Also, we observed that forskolin induced transcription of the IkappaBalpha gene in a time-dependent manner and in addition up-regulated LPS-induced IkappaBalpha mRNA levels. Taken together, this study indicates that the attenuation of LPS-induced iNOS formation in Kupffer cells by elevated intracellular cAMP levels occurs by preventing the degradation of IkappaBalpha which suppresses the activation of NF-kappaB and inhibits the onset of transcription of the iNOS gene.
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PMID:Expression of nitric-oxide synthase in rat Kupffer cells is regulated by cAMP. 947 58

Nitric oxide (NO), initially identified as an endothelium-derived relaxing factor, is a molecular mediator that has been implicated in many physiological and pathological processes. In primary cultured rat glial cells, a combination of inflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta)) and bacterial lipopolysaccharide (LPS) stimulates production of nitrite via expression of the inducible form of nitric oxide synthase (iNOS). In these cells, simultaneous addition of endothelin (ET) markedly inhibited TNF-alpha/IL-1beta-induced and LPS-induced nitrite production and iNOS expression, although ET by itself had no effect. The inhibitory effect of ETs appears to be mediated by ET(B) receptors. Forskolin also inhibited the iNOS expression. By contrast, pretreatment with ET for 24 hours enhanced LPS-induced nitrite production and iNOS expression. This stimulatory effect of ETs was suppressed by calphostin C, a protein kinase C inhibitor, and pretreatment with phorbol ester enhanced LPS-induced iNOS expression. Our findings present the possibility that ET has dual effects on iNOS expression in glial cells.
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PMID:Regulation of inducible NO synthase expression by endothelin in primary cultured glial cells. 958 24

To examine the production of hepatocyte growth factor (HGF) by human endometrial stromal cells (ESC) in vitro, concentrations of HGF in the culture media of ESC were measured after the addition of various amounts of 12-O-tetradecanoylphorbol 13-acetate (TPA), forskolin, lipopolysaccharide (LPS), interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNFalpha), interferon-gamma (IFNgamma), or ethynylestradiol-17alpha using an ELISA. The expression of HGF mRNA was also assayed by a reverse transcription-polymerase chain reaction. The concentration of HGF in the culture media of unstimulated ESC was below the detection level of the assay. TPA stimulated the secretion of HGF by ESC in a dose-dependent manner. TPA also induced the transcription of HGF mRNA by ESC. Forskolin, LPS, IL-1beta, IL-6, IL-8, TNFalpha, IFNgamma, or ethynylestradiol-17alpha did not alter HGF mRNA or protein levels. TPA-stimulated production of HGF was partially inhibited by the addition of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine or sphingosine. These results suggest that a protein kinase C-dependent pathway may play an important role in the regulation of HGF production by ESC. HGF secreted by ESC may be involved in the regeneration of the endometrium during the normal menstrual cycle.
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PMID:Expression of hepatocyte growth factor in cultured human endometrial stromal cells is induced through a protein kinase C-dependent pathway. 1020 81

To clarify the biological and pathological features of choriocarcinoma, we evaluated the in vitro production of cytokines by a choriocarcinoma cell line, BeWo. We measured the concentration of interleukin (IL)-6 and IL-8 in the culture media of BeWo cells after stimulation with various modulatory agents of cytokine expression by enzyme-linked immunosorbent assays. Northern blot analysis was used to examine the expression of IL-6 and IL-8 mRNA in these cells. A weak expression of IL-6 and IL-8 was detected in unstimulated BeWo cells by both methods. IL-6 transcription and secretion were dose-dependently enhanced by stimulation with IL-1beta, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 and 12-O-tetradecanoyl phorbol-13-acetate (TPA). Forskolin, lipopolysaccharide and interferon-gamma had no effect on these cytokines production. The TNF-alpha-induced secretion of IL-6 was inhibited by dexamethasone. The TPA-induced production of IL-6 was inhibited by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and sphyngosine, suggesting the involvement of a protein kinase C-dependent pathway. Levels of IL-8 mRNA and protein were also dose-dependently increased by stimulation with IL-1beta, TNF-alpha and TPA. In contrast to IL-6, the expression of IL-8 was not affected by TGF-beta1. It is suggested that, in addition to the production of steroidal and non-steroidal hormones, these cytokines may serve as part of a cytokine network that modulates the proliferation and angiogenesis of choriocarcinomas.
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PMID:Production of interleukin (IL)-6 and IL-8 by a choriocarcinoma cell line, BeWo. 1083 70

We studied the effects of the phosphodiesterase inhibitors pentoxifylline (PTX) and rolipram (ROL) on nitric oxide (NO) production by macrophages and correlated this with cellular cAMP levels. The RAW 264.7 cell line or mouse peritoneal macrophages were activated with lipopolysaccharide (LPS) and interferon gamma (IFN gamma), with or without ROL, PTX, cAMP analogues, or Forskolin. In vivo, peritoneal macrophages were stimulated with staphylococcal enterotoxin B with or without administration of ROL. Nitrite levels in culture and the total cellular cAMP levels were measured. ROL and PTX suppressed NO production of LPS/IFN gamma-stimulated macrophages. ROL (IC(50) = 68-74 microM) was about 40 times more potent than PTX (IC(50) = 2.4-2.9 mM). The suppression paralleled increased total cellular cAMP level (EC(50) = 68-72 microM) and was mimicked by other cAMP elevating agents. ROL and PTX suppressed inducible NO synthase at the mRNA level. The inhibition of NO production of macrophages by ROL or PTX could be beneficial in NO-mediated inflammatory and/or autoimmune disorders.
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PMID:The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophage activation and nitric oxide production in vitro and in vivo. 1116 85

The effects of some cAMP-elevating agents on the induction of nitric oxide synthase II (NOS II) were investigated for a macrophage-derived cell line, RAW264.7, stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and the results were compared for the case of vascular smooth muscle cells (VSMC) stimulated with interleukin-1 beta (IL-1 beta). Forskolin, dibutyryl cAMP, and a phosphodiesterase inhibitor, 3-isobutyl-1-methyl xanthine, resulted in an elevated production of nitrite and nitrate, NOS II activities, NOS II mRNA accumulation, and the protein level in RAW264.7 cells stimulated with LPS or IFN-gamma. However, the addition of combinations of these reagents decreased these levels in RAW264.7 cells, but enhanced them in VSMC that had been stimulated with IL-1 beta. When intracellular cAMP levels in VSMC were measured, they were elevated by about 100 times more in the forskolin-treated cells, compared to the untreated cells. Stimulated RAW264.7 cells, on the other hand, produced much lower levels of cAMP than VSMC. It is likely that cAMP functions in two opposing directions in terms of NOS II gene induction in RAW264.7 cells in a dose-dependent manner. The effects of cAMP-elevating agents on promoter activities of the 5'-flanking region of the mouse NOS II gene were then examined. The promoter activities were enhanced in RAW264.7 cells, even in the presence of all three cAMP-elevating agents. Although the binding of NF-kappa B to responsive elements is essential for the induction of the NOS II gene, cAMP-elevating agents had no effect on NF-kappa B binding to the element, thus eliminating the involvement of NF-kappa B in the suppression of the NOS II gene by high concentrations of cAMP. These data suggest that a putative responsive element to high levels of cAMP is present outside of the region examined in this study. The inhibitory effects of cAMP in RAW264.7 cells would be due to the presence of a negative regulatory factor that is absent in VSMC.
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PMID:Effect of cAMP on inducible nitric oxide synthase gene expression: its dual and cell-specific functions. 1121 68

The pro-opiomelanocortin-derived peptide alpha-melanocyte-stimulating hormone (alpha-MSH) mediates broad anti-inflammatory and immunomodulatory effects, which include inhibition of the production and release of proinflammatory cytokines and nitric oxide (NO) from macrophages. We investigated the effects of alpha-MSH, alpha-MSH(1-10), and alpha-MSH(11-13) on NO production and nuclear factor-kappaB (NF-kappaB) translocation in RAW 264.7 macrophages. After stimulation of the cells with bacterial lipopolysaccharide/interferon-gamma (LPS/IFN-gamma), all three peptides inhibited NO production with an order of potency alpha-MSH > or = alpha-MSH(11-13) > alpha-MSH(1-10). All three MSH peptides inhibited NF-kappaB nuclear translocation with the maximal effect of alpha-MSH and alpha-MSH(11-13) being seen in the range 1 nM-1 microM, and that of alpha-MSH(1-10) at 1 microM. By use of (125)I-(Nle(4),D-Phe(7))alpha-MSH(NDP-MSH) radioligand binding, MC(1) receptor-binding sites were demonstrated on RAW 264.7 cells. alpha-MSH and alpha-MSH(1-10) competed with the (125)I-NDP-MSH binding at these MC(1) receptor-binding sites, but alpha-MSH(11-13) even in concentrations up to 1 mM did not. Moreover, alpha-MSH and alpha-MSH(1-10) caused powerful stimulation of cyclic 3',5'-adenosine monophosphate (cAMP) in the RAW 264.7 cell, whereas alpha-MSH(11-13) was ineffective. Forskolin stimulated cAMP and inhibited NO production to the same extent as alpha-MSH and alpha-MSH(1-10), but did not modify the translocation of NF-kappaB. Whereas the protein kinase A inhibitor H89 did not modify the effect of alpha-MSH on NF-kappaB translocation, H89 caused a partial inhibition of the inhibitory effect of alpha-MSH, alpha-MSH(1-10), alpha-MSH(11-13), and forskolin on NO production. In addition alpha-MSH, alpha-MSH(1-10), alpha-MSH(11-13), and forskolin also inhibited the activity of an NF-kappaB-dependent luciferase reporter and these effects were partially counteracted by H89. We suggest that melanocortin peptides act via dual mechanisms of action: one cAMP-independent and causing inhibition of NF-kappaB translocation and the other dependent on MC(1) receptor/cAMP activation.
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PMID:Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. 1123 5

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