Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage-colony stimulating factor (M-CSF) contributes to atherogenesis by regulating macrophage-derived foam cells in atherosclerotic lesions. Here we report that nitric oxide (NO) inhibits the expression of M-CSF in human vascular endothelial cells independent of guanylyl cyclase activation. The induction of M-CSF mRNA expression by either oxidized low density lipoprotein (ox-LDL) or tumor necrosis factor-alpha (TNF alpha) was attenuated by NO donors, S-nitrosoglutathione (GSNO), sodium nitroprusside (SNP), and 3-morpholinosydnonimine, but not by cGMP analogues, glutathione, or nitrite. Inhibition of endogenous NO production by N-monomethyl-L-arginine (L-NMA) also increased M-CSF expression in control and TNF alpha-stimulated cells. Nuclear run-on assays and transfection studies using M-CSF promoter constructs linked to chloramphenicol acetyltransferase reporter gene indicated that NO repressed M-CSF gene transcription through nuclear factor-kappa B (NF-kappa B). Electrophoretic mobility shift assays demonstrated that activation of NF-kappa B by L-NMA, ox-LDL, and TNF alpha was attenuated by GSNO and SNP, but not by glutathione or cGMP analogues. Since the induction of M-CSF expression depends upon NF-kappa B activation, the ability of NO to inhibit NF-kappa B activation and M-CSF expression may contribute to some of NO's antiatherogenic properties.
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PMID:Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells. 762 26

Human neutrophils were activated by the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) to produce superoxide (O2-) and to release the primary granule enzyme beta-glucuronidase and the predominantly secondary granule enzyme lysozyme. Pretreatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the secretion of all three substances upon addition of fMLP. The augmentation by GM-CSF was significantly attenuated by the 5-lipoxygenase inhibitor AA861 and by the guanylate cyclase inhibitor LY83583. The secretion induced by fMLP alone was much less affected by either of the two inhibitors. AA861 inhibited leukotriene B4 production in neutrophils primed with GM-CSF and stimulated with fMLP, and LY83583 inhibited GM-CSF-evoked increases of 3',5'-guanosine monophosphate. The data suggest that activation of lipoxygenase and guanylate cyclase is not critical to the fMLP stimulation pathway, but they may be important components of the pathway by which GM-CSF augments neutrophil responses to fMLP. However, AA861 and LY83583 may have important actions in addition to inhibition of 5-lipoxygenase and guanylate cyclase.
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PMID:Effects of inhibition of lipoxygenase and guanylate cyclase on human neutrophil responses to formyl peptide and granulocyte-macrophage colony-stimulating factor. 810 55

During infection, bacterial products, such as lipopolysaccharide (LPS), and viral products release cytokines from immune cells. These cytokines reach the brain by several routes. Furthermore, cytokines such as interleukin-1 (IL-1) are induced in central nervous system neurons by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion which occurs in infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (NOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing-hormone-releasing hormone (LHRH) from neurons, thereby blocking pulsatile luteinizing hormone (LH), but not follicle-stimulating hormone release, and also inhibiting sexual behavior which is induced by LHRH. IL-1 alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) block the response of the LHRH terminals to NO. GM-CSF inhibits LHRH release by acting on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABA-A receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. This concept is supported by a blockade of GM-CSF-induced suppression of LHRH release from medial basal hypothalamic explants by the GABA-A receptor blocker, bicuculline. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone release mediated by NO and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of prolactin release is also mediated by intrahypothalamic action of NO which inhibits release of the prolactin-inhibiting hormone, dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase liberating cyclic guanosine monophosphate and activation of cyclooxygenase and lipoxygenase, with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in the release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part, via induction of inducible NOS. The NO produced alters the release of anterior pituitary hormones.
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PMID:Nitric oxide controls the hypothalamic-pituitary response to cytokines. 948 1

Monocyte-to-macrophage differentiation with the cytokine granulocyte-macrophage colony-stimulating factor induces expression of the cyclic nucleotide phosphodiesterase PDE1B2. However, what role PDE1B2 plays in macrophage biology has not been elucidated. We have addressed this question by inhibiting PDE1B2 induction by using RNA interference. Using a retrovirus-based system, we created HL-60 stable cell lines that express a short-hairpin RNA targeting PDE1B2. HL-60 cells treated with phorbol-12-myristate-13-acetate differentiate to a macrophage-like phenotype and up-regulate PDE1B2. However, expression of PDE1B2 short hairpin RNA effectively suppresses PDE1B2 mRNA, protein, and activity up-regulation. Using the HL-60 PDE1B2 knockdown cells and agonists for either adenylyl or guanylyl cyclase, it was found that PDE1B2 predominantly regulates cGMP and plays a lesser role in cAMP regulation in response to cyclase agonists. Furthermore, in intact HL-60 cells, PDE1B2 activity can be regulated by changes in Ca+2 levels. Inhibiting PDE1B2 up-regulation does not prevent HL-60 cell differentiation, because several markers of macrophage differentiation are unaffected. However, suppression of PDE1B2 expression alters some aspects of the macrophage-like phenotype, because cell spreading, phagocytic ability, and CD11b expression are augmented. The cAMP analog 8-Bromo-cAMP reverses the changes caused by PDE1B2 knockdown. Also, PDE1B2 knockdown cells have lower basal levels of cAMP and alterations in the phosphorylation state of several probable PKA substrate proteins. Thus, the effects of PDE1B2 on differentiation may ultimately be mediated through decreased cAMP. In conclusion, PDE1B2 regulates a subset of phenotypic changes that occur upon phorbol-12-myristate-13-acetate-induced differentiation and likely also plays a role in differentiated macrophages by regulating agonist-stimulated cGMP levels.
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PMID:PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte. 1640 68