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)

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

The liver contains the largest pool of cytokine-producing macrophages in the body and may therefore play an important role in the development and outcome of systemic inflammatory response syndromes. Therefore, we investigated the tumor necrosis factor-alpha (TNF) releasing capacity of the in situ perfused mouse liver and its modulation by methylxanthines, i.e., by a class of well-established inflammatory cytokine-suppressing drugs. We have shown that pretreatment of mice with either lipopolysaccharide or TNF elicited a dose-dependent TNF release into the perfusate which was inhibited by in vivo pretreatment of mice with pentoxifylline or A-802715 [1-(5-hydroxy-5-methyl)hexyl-3-methyl-7-propylxanthin]. Infusion of these methylxanthines into livers from mice pretreated with lipopolysaccharide or TNF also inhibited TNF release in an immediate and reversible way even after TNF production had been initiated. The inhibitory effect of methylxanthines was prevented by pretreatment of mice with the adenylate cyclase inhibitor dideoxyadenosine, suggesting upregulation of the cyclic adenosine monophosphate system as a possible mechanism of action of these drugs. Our findings demonstrate that the liver is a potent cytokine producer and identify it as one of the target organs of methylxanthines or other phosphodiesterase inhibitors in murine models of shock and inflammatory liver failure.
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PMID:Tumor necrosis factor production in the perfused mouse liver and its pharmacological modulation by methylxanthines. 878 77

The enhanced nitric oxide (NO) and prostaglandin (PG) generation of activated macrophages is controlled by glucocorticoid-sensitive inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Negative feedback regulation of iNOS expression by the products of both pathways has been suggested, but their effects on COX-2 expression have not been examined. We hae investigated the effect of E- and l-series prostaglandins that activate adenylate cyclase (AC), forskolin (a direct activator of AC), and other agents that influence the cyclicAMP/cyclicGMP systems on the ability of E. coli endotoxin (lipopolysaccharide, LPS) to induce iNOS and COX-2 in the murine macrophage cell line J774. After a 2-hr pretreatment before adding endotoxin, PGE2, PGI2, forskolin, IBMX (isobutylmethylxanthine, a cyclicAMP/cyclicGMP phosphodiesterase inhibitor), 8-bromo cyclicAMP, and arachidonic acid itself all inhibited the expression of both iNOS and COX-2 (as shown by Western blotting) and reduced NO release and COX activity, whereas PGF2 alpha and 8-bromo cyclic GMP were only weakly effective. The effects of PGE2, PGI2, and forskolin were enhanced by cotreatment with IBMX. The suppression of LPS-induced iNOS induction by PGE2 was functionally significant, in that it protected against the mild cytotoxicity of the NO generated in response to endotoxin. These results provide the first direct evidence for the feedback regulatory suppression of COX-2 induction by a PG-driven cAMP-mediated process, and show that the modulation of iNOS and COX-2 induction shares common features. They also suggest that such modulation is normally held in check by high phosphodiesterase activity within these cells.
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PMID:Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages. 910

Addition of lipopolysaccharide plus interferon gamma, tumour necrosis factor alpha and interleukin 1 beta to cultured hepatocytes resulted in the induction of inducible nitric oxide synthase (iNOS) activity as measured by NO3(-)+NO2- formation, the conversion of L-[U-14C]arginine into citrulline and Western blotting of the iNOS protein. The inclusion of 1 microM glucagon during the induction period significantly decreased the effect of the cytokines on iNOS activity, the major effect being at the level of the total amount of protein, rather than alterations in substrate supply or covalent modification of the existing protein. In contrast, 1 microM insulin was without effect. The effect of glucagon was mediated via cAMP and could be mimicked by the presence of either dibutyryl cAMP or forskolin to activate adenylate cyclase directly. It was rapid in onset and long-lived, a 30 min pretreatment period protecting the cells from the induction of NO synthesis over the next 21 h in the presence of cytokines. Addition of glucagon at any time point up to 9 h after treatment of the cells with lipopolysaccharide plus the cytokines resulted in a significant inhibition of iNOS activity, glucagon being most potent when added during the first 3 h.
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PMID:Inhibition of cytokine-induced inducible nitric oxide synthase expression by glucagon and cAMP in cultured hepatocytes. 933 67

Tumor necrosis factor-alpha (TNF-alpha) is elevated in the failing heart. Very little is known about regulation of TNF-alpha in cardiomyocytes. TNF-alpha expression by macrophages is diminished by adenosine. Therefore, we hypothesized that a similar mechanism might occur in the heart. Neonatal rat myocytes were stimulated with lipopolysaccharide (LPS), and TNF-alpha was measured by ELISA. In the absence of LPS, myocytes did not release TNF-alpha in the medium. After exposure to LPS, TNF-alpha increased to 70.1+/-3.5 pg/mL at 6 hours. Immunofluorescent staining confirmed that TNF-alpha was expressed in myocytes. Adenosine decreased TNF-alpha in a dose-dependent manner (1 to 100 micromol/L, 37% to 65% decrease, P<.01). Adenosine also decreased TNF-alpha in cell homogenates by 78% (P<.0001). The effect of adenosine could be replicated by the A2 agonist PD-125944 (DPMA), by cAMP agonists 8-bromo-cAMP, forskolin, and Ro 20-1724, but not by A1 and A3 agonists. Conversely, the effect of adenosine could be suppressed by the adenylate cyclase inhibitor MDL-12,330. Adenosine also inhibited TNF-alpha in adult rat ventricular myocytes (-60%, P<.005) and rat papillary muscles (-55%, P<.05). In neonatal myocytes, adenosine normalized LPS-induced calcium changes and improved LPS-induced negative inotropic (P<.01) and negative lusitropic (P<.01) effects. Our results demonstrate that adenosine can significantly diminish TNF-alpha levels in the heart. The effect appears to be mediated by the A2 receptor and transduced through a G protein-adenylyl cyclase pathway. These results may explain some cardioprotective effects of adenosine and provide a novel pharmacological intervention in congestive heart failure.
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PMID:Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. 944 Jul 4

Microglial cell activation plays a central role in acute and chronic inflammatory processes associated with neurodegeneration. As macrophage activation is generally associated with the up-regulation of specific surface antigens, the expression of CD54, and CD29 were evaluated on CD11b positive neonatal rat microglial cell cultures by flow cytometry. These cells when exposed to lipopolysaccharide, LPS, and gamma interferon, IFN gamma, exhibited a 2-3 fold increase in CD54 expression, an increase in CD29 and no change in CD11b. Maximal increases in CD54 and CD29 staining on CD11b positive microglial cells were apparent 20-24 h after LPS and IFN gamma while nitrite production reflecting inducible nitric oxide synthase activity, continued to increase. The increases in CD29 and CD54 staining were inhibited in a dose dependent manner by agents which increased intracellular cAMP levels including 100 microM 8-bromoadenosine 3':5'-cyclic monophosphate but not 8-bromoadenosine monophosphate, the phosphodiesterase inhibitor isobutyl methylxanthine and by direct activation of adenylate cyclase with forskolin. Concomitant with the dose dependent decreases in CD29 and CD54 staining were increases in intracellular cAMP and reduced TNF secretion. These results suggest that regulation of CD29 and CD54 expression on activated microglial cells involves a cAMP dependent pathway.
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PMID:Expression of CD54 (intercellular adhesion molecule-1) and the beta 1 integrin CD29 is modulated by a cyclic AMP dependent pathway in activated primary rat microglial cell cultures. 948 53

Adrenomedullin (AM) has very recently been demonstrated to be produced and secreted from fibroblasts. The production of AM in the fibroblasts is augmented by inflammation-related substances, and Swiss 3T3 fibroblast cells express AM specific receptors coupled with adenylate cyclase. To assess the functions of AM secreted from fibroblasts, we measured the effect of AM on production in Swiss 3T3 cells of interleukin-6 (IL-6), a typical cytokine involved in the general inflammatory reactions. AM stimulated basal secretion of IL-6 5.5-fold, while other peptides elicited much weaker stimulatory effects. The effect of AM was inhibited with an AM receptor antagonist and a cAMP-dependent protein kinase (PKA) inhibitor. Furthermore, AM remarkably potentiated stimulatory effects of tumor necrosis factor-alpha, IL-1 beta and lipopolysaccharide on IL-6 production. This stimulatory effect of AM was induced through activation of gene transcription, which reached maximum within 30 min. These findings verify that AM is a rapid and extraordinarily potent regulator of IL-6 production in Swiss 3T3 cells acting through the cAMP-PKA pathway. The data thus obtained suggest that AM is a peptidergic regulator of inflammation.
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PMID:Adrenomedullin stimulates interleukin-6 production in Swiss 3T3 cells. 951 21

Immune suppression by cannabinoids has been widely demonstrated in a variety of experimental models. The identification of two major types of G-protein-coupled cannabinoid receptors expressed on leukocytes, CB1 and CB2, has provided a putative mechanism of action for immune modulation by cannabinoid compounds. Ligand binding to both receptors negatively regulates adenylate cyclase, thereby lowering intracellular cyclic AMP (cAMP) levels. In the present studies, we demonstrated that cannabinol (CBN), a ligand that exhibits higher binding affinity for CB2, modulates immune responses and cAMP-mediated signal transduction in mouse lymphoid cells. Direct addition of CBN to naive cultured splenocytes produced a concentration-dependent inhibition of lymphoproliferative responses to anti-CD3, lipopolysaccharide, and phorbol-12-myristate-13-acetate/ionomycin stimulation. Similarly, a concentration-related inhibition of the in vitro anti-sheep red blood cell IgM antibody forming cell response was also observed by CBN. Evaluation of cAMP signaling in the presence of CBN showed a rapid and concentration-related inhibition of adenylate cyclase activity in both splenocytes and thymocytes. This decrease in intracellular cAMP levels produced by CBN resulted in a reduction of protein kinase A activity, consequently leading to an inhibition of transcription factor binding to the cAMP response element and kappaB motifs in both cell preparations. Collectively, these results demonstrate that CBN, a cannabinoid with minimal CNS activity, inhibited both cAMP signal transduction and immune function, further supporting the involvement of CB2 receptors in immune modulation by cannabimimetic agents.
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PMID:Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappaB elements by cannabinol, a minimally CNS-active cannabinoid. 960 25

Nitric oxide (NO) production regulates vasodilation in many blood vessels. Additionally, constitutive NO release is being associated with positive biomedical phenomena, whereas inducible NO synthase (iNOS)-associated NO release with detrimental consequences in regard to endothelial inflammatory activities. As yet, an important link demonstrating why one is activated over the other is not available. Previous studies have demonstrated that morphine and anandamide effector processes are coupled to NO release in human endothelial cells (ECs). This study now extends this observation in that these endogenous signaling molecules may use NO directly to inhibit adenylate cyclase activity. Activation of human ECs, obtained from the saphenous vein, with morphine- or anandamide-stimulated NO release (35 nM and 28 nM, respectively) that peaked within 5 min and returned to basal levels within 10 min of agonist stimulation, consistent with constitutive NO synthase (cNOS) activation. Significant release of NO from ECs stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) occurred after 2 h after exposure and remained significantly increased over basal levels for 24-48 h (28 nM), consistent with iNOS activation. Preincubation of ECs with morphine or anandamide before, but not after, the addition of LPS + IFN, blocked iNOS activity. Exposure of ECs to the NO donor, SNAP, before the addition of LPS + IFN, blocked iNOS induction, whereas preincubation of ECs with inhibitors of NOS, before morphine or anandamide exposure, restored LPS + IFN induction of iNOS, suggesting a direct impact of NO on the regulation of iNOS activity. Morphine and anandamide stimulation of ECs did not stimulate cyclic adenosine monophosphate (cAMP) accumulation, whereas a marked increase in cAMP was observed in ECs treated with LPS + IFN (8.2 to 33 pmol/mg protein). Treatment of ECs with LPS + IFN did not induce cAMP accumulation in ECs treated with morphine, anandamide, or SNAP before LPS + IFN exposure. These data suggest that cAMP is required for the induction of iNOS in ECs and that NO may directly impair adenylate cyclase activity, preventing iNOS activation.
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PMID:Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. 964 64

Tumor necrosis factor alpha (TNFalpha), an early cytokine produced by activated macrophages, plays an essential role in normal and pathological inflammatory reactions. The excessive production of TNFalpha is prevented by the so-called "macrophage-deactivating factors." This study examines the role of two structurally related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating peptide (PACAP), as inhibitors of TNFalpha. Both VIP and PACAP inhibit TNFalpha production from lipopolysaccharide-stimulated RAW 246.7 cells in a dose- and time-dependent manner. Although the activated cells express mRNA for all three VIP/PACAP receptors, agonist and antagonist studies indicate that the major receptor involved is VIP1R. VIP/PACAP inhibit TNFalpha gene expression by affecting both NF-kB binding and the composition of the cAMP responsive element binding complex (CREB/c-Jun). Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of TNFalpha gene expression and appear to differentially regulate the transcriptional factors involved. Because TNFalpha plays a central role in various inflammatory diseases such as endotoxic shock, multiple sclerosis, cerebral malaria, and various autoimmune conditions, the down-regulatory effect of VIP/PACAP may have a significant therapeutic potential.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. 981 54


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