Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired renal cysts derive from terminally differentiated tubular epithelium in adults as a consequence of increased epithelial cell proliferation, fluid accumulation and extracellular matrix remodelling. To understand better how human epithelial cysts may be initiated and progressively expand, cells from primary cultures of normal human adult renal cortex were dispersed in polymerized type I collagen. The transparent matrix permitted repeated observation by light microscopy of cyst formation from individual renal cells. The cyst cells reacted strongly with distal nephron histochemical markers (cytokeratin antibodies AE1/AE3, epithelial membrane antigen, and Arachis hypogaea lectin) but inconsistently or not at all to markers of proximal tubules (Tetragonolobus purpureas lectin and Phaseolus vulgaris erthroagglutinin lectin). The number of spherical, fluid-filled epithelial cysts that developed in a standardized microscope field quantified cyst initiation. Cyst progression was determined from the increase in the diameter (surface area) of cysts and represents a hyperplastic event. EGF or TGF alpha, were required in serum-free defined medium to cause cysts to develop from individual epithelial cells dispersed in the matrix; insulin was required as a co-factor. The EC50 for EGF was approximately 0.1 ng/ml, and for insulin 1 microgram/ml. Early cultures of normal cortex formed cysts more efficiently when dispersed in collagen matrix than cells passaged several times before suspension in the gel. Agonists of adenylate cyclase (PGE1, AVP, VIP, PTH, forskolin, cholera toxin), methylisobutylxanthine, and 8-Br-cAMP, though incapable of causing cyst formation alone in defined medium, enhanced cyst initiation and progression in the presence of EGF and insulin. Angiotensin II, TNF alpha, beta-estradiol, and pertussis toxin had no effect in the absence or presence of EGF and insulin. Pertussis toxin inhibited cyst initiation and expansion caused by EGF and forskolin but potentiated cyst initiation and expansion caused by EGF and PGE1. Cyst formation and expansion were inhibited by TGF beta 1 and 2-chloroadenosine. Polarized monolayers of human renal cortical cells grown on permeable membranes were used to independently quantify the effects of agonists on the net secretion of solute and water from the basolateral to the apical surface of the cells. PGE1, forskolin, and 8-Br-cAMP stimulated net fluid secretion that was sustained for several days; EGF enhanced forskolin-stimulated fluid secretion. We conclude that the formation and expansion of in vitro cysts derived from solitary human cortex cells depends on the coordinated interplay between cellular proliferation and fluid secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro formation and expansion of cysts derived from human renal cortex epithelial cells. 131 21

We sought to establish and immunocytochemically characterize primary cultures of human conjunctival epithelial (HCE) cells, and to determine the types of receptors coupled to adenylate cyclase (AC) and phospholipase C (PLC) present on them which may be stimulated following allergic or inflammatory provocation of the tissue. HCE cells possessed the key epithelial cell surface cytokeratins AE1, AE3 and AE5. Signal transduction studies (n > or = 3), using agonists and antagonists, revealed the presence of beta 2-adrenergic (isoproterenol EC50 = 5.2 nM), prostaglandin E2 (EC50 = 168 nM) and vasoactive intestinal peptide (EC50 = 0.69 nM) receptors positively coupled to AC in HCE cells. Bradykinin (EC50 = 0.83 nM), platelet activating factor (EC50 = 4.5 nM), leukotriene C4 (EC50 = 300 nM) and histamine1 (EC50 = 3.1 microM) receptors were coupled to PLC (n = 3 for each). These data suggest that HCE cells in vivo may represent target cells for mast cell mediators and certain neurotransmitters which are released into the tear-film upon allergic provocation of the conjunctiva.
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PMID:Pharmacological analysis of mast cell mediator and neurotransmitter receptors coupled to adenylate cyclase and phospholipase C on immunocytochemically-defined human conjunctival epithelial cells. 926 68

Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE(2) on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE(2) to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE(2) receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE(2) on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1-259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE(2), while ONO-AE1-329 (EP4R agonist) was much less potent than PGE(2). The EP2/EP4R agonist 11-deoxy-PGE(1) mimicked the effect of PGE(2) with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE(2). Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE(2) down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE(2) may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.
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PMID:Prostaglandin E(2) inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells. 1197 Sep 88

Effects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors. Proliferation of VSMCs was assessed by measuring [(3)H]-thymidine incorporation and the cell number, and their hypertrophy by [(14)C]-leucine incorporation and protein content. In VSMCs from wild-type mice, expressions of mRNAs for the EP(4) and TP were most abundant, followed by those for the IP, EP(3) and FP, when examined by competitive reverse transcriptase-PCR. Those for the EP(1), EP(2) and DP, however, could not be detected. AE1-329, an EP(4) agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor (PDGF)-induced proliferation of VSMCs from wild-type mice; these inhibitory effects disappeared completely in VSMCs from EP(4)(-/-) and IP(-/-) mice, respectively. In accordance with these effects, AE1-329 and cicaprost stimulated cAMP production in VSMCs from wild-type mice, which were absent in VSMCs from EP(4)(-/-) and IP(-/-) mice, respectively. Effects of PGE(2) on cell proliferation and adenylate cyclase were almost similar with those of AE1-329 in VSMCs from wild-type mice, which disappeared in VSMCs from EP(4)(-/-) mice. PGD(2) inhibited PDGF-induced proliferation of VSMCs from both wild-type and DP(-/-) mice to a similar extent. This action of PGD(2) was also observed in VSMCs from EP4(-/-) and IP(-/-) mice. In VSMCs from wild-type mice, I-BOP, a TP agonist, showed potentiation of PDGF-induced hypertrophy. I-BOP failed to show this action in VSMCs from TP(-/-) mice. The specific agonists for the EP(1), EP(2) or EP(3), and PGF(2)alpha showed little effect on the growth of VSMCs. These results show that PGE(2), PGI(2) and TXA(2) modulate PDGF-induced proliferation or hypertrophy of VSMCs via the EP(4), IP and TP, respectively, and that the inhibitory effect of PGD(2) on PDGF-induced proliferation is not mediated by the DP, EP(4) or IP.
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PMID:Effects of the prostanoids on the proliferation or hypertrophy of cultured murine aortic smooth muscle cells. 1205 31

Prostaglandin E(2) is a potent lipid mediator of inflammation that effects changes in cell functions through ligation of four distinct G protein-coupled receptors (E-prostanoid (EP)1, EP2, EP3, and EP4). During pneumonia, PGE(2) production is enhanced. In the present study, we sought to assess the effect of endogenously produced and exogenously added PGE(2) on FcRgamma-mediated phagocytosis of bacterial pathogens by alveolar macrophages (AMs), which are critical participants in lung innate immunity. We also sought to characterize the EP receptor signaling pathways responsible for these effects. PGE(2) (1-1000 nM) dose-dependently suppressed the phagocytosis by rat AMs of IgG-opsonized erythrocytes, immune serum-opsonized Klebsiella pneumoniae, and IgG-opsonized Escherichia coli. Conversely, phagocytosis was stimulated by pretreatment with the cyclooxygenase inhibitor indomethacin. PGE(2) suppression of phagocytosis was associated with enhanced intracellular cAMP production. Experiments using both forskolin (adenylate cyclase activator) and rolipram (phosphodiesterase IV inhibitor) confirmed the inhibitory effect of cAMP stimulation. Immunoblot analysis of rat AMs identified expression of only EP2 and EP3 receptors. The selective EP2 agonist butaprost, but neither the EP1/EP3 agonist sulprostone nor the EP4-selective agonist ONO-AE1-329, mimicked the effects of PGE(2) on phagocytosis and cAMP stimulation. Additionally, the EP2 antagonist AH-6809 abrogated the inhibitory effects of both PGE(2) and butaprost. We confirmed the specificity of our results by showing that AMs from EP2-deficient mice were resistant to the inhibitory effects of PGE(2). Our data support a negative regulatory role for PGE(2) on the antimicrobial activity of AMs, which has important implications for future efforts to prevent and treat bacterial pneumonia.
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PMID:Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP. 1521 Aug 17

Advanced glycation end product (AGE) subtypes, proteins or lipids that become glycated after exposure to sugars, induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) have been indicated to play roles in inflammation in diabetic patients. The engagement of AGEs and receptor for AGEs activates monocytes. Because the engagement of intercellular adhesion molecule-1 (ICAM-1), B7.1, B7.2, and CD40 on monocytes with their ligands on T cells plays roles in cytokine production, we investigated the effects of AGE-2 and AGE-3 on the expressions of ICAM-1, B7.1, B7.2, and CD40 on monocytes, the production of interferon gamma and tumor necrosis factor alpha, and the lymphocyte proliferation in human peripheral blood mononuclear cells and their modulation by prostaglandin E(2) (PGE(2)). AGE-2 and AGE-3 induced the expressions of adhesion molecule, the cytokine production, and the lymphocyte proliferation. PGE(2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE(2) were mimicked by an E-prostanoid (EP)(2)-receptor agonist, 11,15-O-dimethyl prostaglandin E(2) (ONO-AE1-259-01), and an EP(4) receptor agonist, 16-(3-methoxymethyl)phenyl-omega-tetranor-3,7-dithia prostaglandin E(1) (ONO-AE1-329). An EP(2)-receptor antagonist, 6-isopropoxy-9-oxaxanthene-2-carboxylic acid (AH6809), and an EP(4)-receptor antagonist, (4Z)-7-[(rel-1S,2S,5R)-5-(1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH23848), inhibited the actions of PGE(2). The stimulation of EP(2) and EP(4) receptors is reported to increase cAMP levels. The effects of PGE(2) were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by a dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicated that PGE(2) inhibited the actions of AGE-2 and AGE-3 via EP(2)/EP(4) receptors and the cAMP/PKA pathway.
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PMID:Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells. 1970 Jun 29

Posttransplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays a role in diabetes complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T cells, reducing allograft survival. In previous work, we found that toxic AGEs, AGE-2 and AGE-3, induced the expression of intracellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes, production of interferon-gamma and tumor necrosis factor alpha, and lymphocyte proliferation during human mixed lymphocyte reaction. AGE-induced up-regulation of adhesion molecule expression was involved in cytokine production and lymphocyte proliferation. Prostaglandin E2 (PGE2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE2 were mimicked by an EP2 receptor agonist, ONO-AE1-259-01 (11,15-O-dimethyl PGE2), and an EP4 receptor agonist, ONO-AE1-329 [16-(3-methoxymethyl)phenyl-omega-tetranor-3,7dithia PGE1]. An EP2 receptor antagonist, AH6809 (6-isopropoxy-9-oxaxanthene-2-carboxylic acid), and an EP4 receptor antagonist, AH23848 [(4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid], inhibited the actions of PGE2. The stimulation of EP2 and EP4 receptors is reported to increase cAMP levels. The effects of PGE2 were reversed by protein kinase A (PKA) inhibitors and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicate that PGE2 inhibited the actions of AGE-2 and AGE-3 via EP2/EP4 receptors and the cAMP/PKA pathway.
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PMID:Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction. 2055 73