Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A common basis to genetic regulation of leishmanial and mycobacterial infections is provided by the action of the murine Lsh/Ity/Bcg gene in controlling the priming/activation of macrophages for antimicrobial activity. This relies on the TNF-alpha-dependent sustained expression of the inducible nitric oxide synthase (iNOS) gene responsible for the generation of large amounts of toxic nitric oxide (NO). The Lsh/Ity/Bcg gene has many pleiotropic effects, including differential expression of the early response gene KC following stimulation of macrophages with bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM). The major signal transduction pathway involved in KC induction requires the generation of low levels of NO via constitutive nitric oxide synthase (cNOS) activity, leading to activation of guanylate cyclase and the cGMP-dependent kinase pathway. NO therefore appears to provide a common link between the early influence of Lsh in regulating the expression of genes which mediate many pleiotropic effects, and the later production of NO as the final effector mechanism for kill. The recently cloned candidate for Lsh/Ity/Bcg, designated Nramp for Natural resistance associated macrophage protein, encodes a polytopic integral membrane protein that has structural features common to prokaryotic and eukaryotic transporters and includes a conserved binding-protein-dependent transport motif which may be involved in interaction with peripheral ATP-binding subunits. The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues. 773 96

We studied the effect of nitric oxide on LPS-induced TNF-alpha production by human neutrophils. Human neutrophils exposed to LPS and IFN-gamma did not show measurable increases in intracellular cyclic GMP (cGMP). However, cGMP increased upto 30-fold (p < 0.01) in neutrophils incubated with both sodium nitroprusside (SNP), an exogenous source of nitric oxide, and N-acetylcysteine (NAC), which increases the bioavailability of nitric oxide; this increase indicates that neutrophils contain a nitric oxide-sensitive guanylate cyclase. SNP, with or without NAC, did not increase TNF-alpha production in human neutrophils cultured in medium alone. However, LPS-dependent TNF-alpha production was increased by exposure to SNP (p < 0.05); this effect was further increased by the addition of NAC (p < 0.02). IFN-gamma greatly increased LPS-mediated TNF-alpha production by human neutrophils (p < 0.01), and SNP plus NAC was found to further augment this production (p < 0.01). The up-regulation of TNF-alpha production by nitric oxide was not associated with increased amounts of LPS-induced TNF-alpha mRNA, and was not reproduced by exposing neutrophils to cGMP analogues. These data suggest that nitric oxide released by endothelial and vascular smooth muscle cells may exert a paracrine effect on human neutrophils and augment the inflammatory response in sepsis by increasing the production of cytokines. Although the mechanism of this effect remains unknown, it does not seem to be dependent on cGMP or increased levels of TNF-alpha mRNA.
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PMID:Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils. 814 75

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expression. In this study we show that BH4 availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrates, an early event which occurred well before the induction of NOS2 could be evidenced. These findings suggest a role for BH4 in the modulation of mesangial cell responses to pro-inflammatory stimuli.
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PMID:Tetrahydrobiopterin modulates cyclooxygenase-2 expression in human mesangial cells. 940 25

Tumor necrosis factor (TNF)-alpha, a pluripotent cytokine implicated in the pathogenesis of airway inflammation, has been shown to provoke hypersecretion of mucin by airway epithelial cells in vitro. In this study, we investigated potential signaling pathways mediating TNF-alpha-induced mucin secretion using guinea pig tracheal epithelial (GPTE) cells in air-liquid interface culture. Exogenously applied TNF-alpha (human recombinant) stimulated mucin secretion in a concentration-dependent manner, with maximal effects at 10 to 15 ng/ml (286 to 429 U/ml). The pathway of stimulated secretion appeared to involve generation of intracellular nitric oxide (NO), activation of soluble guanylate cyclase (GC-S), production of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (PKG). TNF-alpha increased production of nitrite and nitrate by GPTE cells; both mucin secretion and cGMP production were attenuated by NG-monomethyl-L-arginine (1 mM), a competitive inhibitor of nitric oxide synthase (NOS), or by the GC-S inhibitor LY83583 (50 microM); and mucin secretion in response to TNF-alpha or to the cGMP analogue dibutyryl cGMP (100 and 500 microM) was attenuated by the specific PKG inhibitor KT5823 (1 microM). Increased mucin secretion and increased cGMP production in response to TNF-alpha both appeared to be mediated by a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC), and by protein kinase C (PKC), since both responses were attenuated by either D609 (10 and 20 microg/ml), a specific PC-PLC inhibitor, or by each of three PKC inhibitors: Calphostin C (0.3 and 0.5 microM), bisindoylmaleimide (GF 109203X, Go 6850; 20 nM), or Ro31-8220 (10 microM). Collectively, the results suggest that TNF-alpha stimulates secretion of mucin by GPTE cells via a mechanism(s) dependent on PC-PLC and PKC, and involving activation of NOS, generation of NO, production of cGMP, and activation of PKG.
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PMID:Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. 1003 Aug 39

Macrophage activation and the resulting inflammatory response may be a major component of tissue injury upon hypoxia and re-oxygenation. Activation of the haem oxygenase (HO)/carbon monoxide (CO) pathway may be an important regulator of the inflammatory response, through production of cyclic 3', 5'-monophosphate (cGMP). We have assessed whether HO contributes to the increased production of the pro-inflammatory cytokines TNF-alpha and IL-6 in re-oxygenated rat peritoneal macrophages.Hypoxia/re-oxygenation markedly increased levels of HO-1 mRNA and cGMP. The increase in cGMP was reduced by the HO-1 inhibitor tin-protoporphyrin (SnPP-9) given during re-oxygenation. Hypoxia and re-oxygenation also increased IL-6 and TNF-alpha mRNA expression, as well as IL-6 and TNF-alpha concentrations in the cell supernatant. These increases were nullified by SnPP-9 and by Methylene Blue, an inhibitor of guanylate cyclase, but were not affected by L-NNA, an inhibitor of NO synthesis. The inhibitory effect of SnPP on the synthesis of cytokines was reversed by co-administration of the stable analogue of cGMP, 8-Br-cGMP. Our results indicate that activation of haem oxygenase and of the CO/cGMP pathway is a major stimulus for the synthesis and release of pro-inflammatory cytokines in re-oxygenated macrophages. This pathway may play a central role in pathological situations in which local tissue hypoxia/re-oxygenation triggers a systemic inflammatory response, for example in patients with shock.
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PMID:Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP. 1032 72

We tested the hypothesis that NO synthase inhibition alters proinflammatory cytokine expression during acute lung injury in mice. Five-week-old CD-1 mice were pretreated with l-NAME or d-NAME and then received an intratracheal injection of endotoxin (or PBS). TNF-alpha and IL-6 ELISAs and RT-PCR were performed on lung homogenates sampled 6 h later. l-NAME increased TNF-alpha and IL-6 protein and mRNA expression in lungs. Immunostaining demonstrated that TNF-alpha was expressed predominantly by macrophages in the lung. l-NAME did not alter pulmonary macrophage concentration. To better understand the effect of NO synthase inhibition, elicited murine peritoneal macrophages were stimulated in vitro with LPS after addition of l-NAME, d-NAME, nitroprusside, or control. Nuclear proteins were extracted 3 h later and electrophoretic mobility shift and supershift assays were performed using radiolabeled NF-kappaB consensus sequence oligonucleotides. Endotoxin increased NF-kappaB p50/p65 heterodimer binding. Binding was further increased by l-NAME and decreased by nitroprusside. The effect of nitroprusside was not blocked by guanylate cyclase inhibition. We conclude that, in endotoxin-induced acute lung injury, NO synthase inhibition increases proinflammatory cytokine protein and mRNA expression in part because NO decreases the amount of NF-kappaB available for binding to the regulatory region of proinflammatory cytokine genes.
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PMID:Modulation of proinflammatory cytokines by nitric oxide in murine acute lung injury. 1043 Jul 48

The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-alpha. TNF-alpha production in murine bone marrow-derived macrophages was induced by LPS, and TNF-alpha secretion (+/-ANP) was determined by L929 bioassay. ANP dose dependently (10-8-10-6 M) inhibited TNF-alpha release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide "clearance" receptor inhibited TNF-alpha production only at 10-7 and 10-8 M, but not at 10-6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-alpha-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-alpha inhibition, Northern blot was performed. ANP-treated macrophages displayed decreased TNF-alpha-mRNA levels. Besides the known inhibition of NF-kappaB activation, in this study we demonstrated that ANP also attenuates the activation of the proinflammatory transcription factor AP-1 (gel shift assay). ANP did not alter subunit composition of AP-1 complexes, as was shown by supershift assays applying anti-c-jun and anti-c-fos Abs. To get information on the ANP effect for human inflammatory processes, we investigated cytokine production in human LPS-activated blood. ANP significantly attenuated production of TNF-alpha and IL-1beta without affecting production of IL-10 and IL-1ra. In summary, ANP was shown to attenuate TNF-alpha production of LPS-activated macrophages via cGMP. The inhibition is suggested to involve transcriptional processes that are the result of reduced activation of responsible transcription factors.
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PMID:cGMP-mediated inhibition of TNF-alpha production by the atrial natriuretic peptide in murine macrophages. 1086 Oct 50

Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1beta plus tumor necrosis factor (TNF)-alpha reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1beta/TNF-alpha-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
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PMID:Posttranscriptional regulation of human iNOS by the NO/cGMP pathway. 1118 8

Activated hepatic stellate cells play a major role in the pathophysiology of chronic liver disease. They can influence the metabolism of hepatocytes by producing a variety of cytokines and growth factors. Upon stimulation with endotoxin, stellate cells also synthesize nitric oxide (NO), a potent mediator of growth of several cell types including hepatocytes. We investigated the effect of serum-free medium conditioned by activated stellate cells in the absence and presence of endotoxin on NO and DNA synthesis in hepatocytes. Stellate cells and hepatocytes were isolated by enzymatic digestion of the liver. Stellate cells were cultured for 10 days after which the majority exhibited alpha-smooth muscle actin (a marker for activated cells); hepatocytes were used after overnight culture. While the medium conditioned by stellate cells in the absence of endotoxin stimulated DNA synthesis in hepatocytes, medium conditioned in its presence inhibited this process in an endotoxin concentration-dependent manner (10 - 1000 ng ml(-1)). Endotoxin-conditioned stellate cell medium also stimulated NO synthesis in hepatocytes; the effect was consistent with increased protein and mRNA expression of inducible NO synthase (iNOS). However, inhibition of DNA synthesis in hepatocytes caused by endotoxin-conditioned stellate cell medium was unaffected by the NOS inhibitor, L-N(G)-monomethylarginine (L-NMMA), guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and neutralizing antibodies for TGF-beta, IL-1beta, IL-6 and TNF-alpha. These results indicate that factors other than these cytokines produced by activated stellate cells upon stimulation with endotoxin or by hepatocytes challenged with endotoxin-conditioned stellate cell medium inhibit DNA synthesis in hepatocytes.
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PMID:Inhibition of DNA synthesis in cultured hepatocytes by endotoxin-conditioned medium of activated stellate cells is transforming growth factor-beta and nitric oxide-independent. 1148 24

Atrial natriuretic peptide (ANP) is a cardiovascular hormone secreted mainly by the cardiac atria and regulates the volume-pressure homeostasis. The action of ANP is mediated by its receptor, guanylyl cyclase-coupled receptor A (GC-A). In this study, we explored the possibility that ANP and GC-A may play a role in the dendritic cell (DC)-mediated immune regulation. We first examined the expression of GC-A in human monocyte-derived DCs in comparison with monocytes and found that DCs but not monocytes express GC-A at both the mRNA and protein levels. DCs responded to ANP with an increase in intracellular cGMP in a dose-dependent manner, indicating that GC-A expressed on DCs is functional. Furthermore, treatment of DCs with ANP decreased production of IL-12 and TNF-alpha and conversely increased that of IL-10 upon stimulation with LPS. In accordance with this change of cytokine production, DCs treated with ANP plus LPS promoted differentiation of naive CD4(+) T cells into a Th2 phenotype. Finally, we presented evidence that ANP affected cytokine production of fresh whole blood stimulated with LPS in line with the above-mentioned results. These results indicate that ANP polarizes human DCs toward a Th2-promoting phenotype through GC-A and thus can regulate immune responses.
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PMID:Atrial natriuretic peptide polarizes human dendritic cells toward a Th2-promoting phenotype through its receptor guanylyl cyclase-coupled receptor A. 1279 12


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