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)

Mouse macrophages and macrophage cell lines such as P388D1 or J774 carry at least two distinct Fc gamma receptors (Fc gamma R): one specific for the Fc portion of IgG2a (Fc gamma aR, also classified as Fc gamma RI) and another for IgG2b (Fc gamma 2bR, also classified as Fc gamma RII beta). These Fc gamma Rs should transmit, upon binding of an appropriate ligand, a specific signal that leads to the regulation of macrophage functions, as the interaction of immune complex with cell surface receptor has been shown to lead to suppression of the humoral immune response or B cell differentiation, to the destruction of target cells by antibody-dependent cell-mediated cytotoxicity, to activation of arachidonic acid metabolic cascade, to the phagocytosis of opsonized particles, or to the generation of superoxide anion. In this review, we first describe evidence that Fc gamma 2aR and Fc gamma 2bR are associated with casein kinase II and phospholipase A2 activity, respectively. We will then discuss a potential role for these enzymatic activities in signal transduction pathways that leads to the activation of the arachidonic acid metabolic cascade and adenylate cyclase, to the regulation of phagocytosis, and to the suppression of interferon-gamma action to induce Ia antigens.
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PMID:Signal transduction mechanisms through Fc gamma receptors on the mouse macrophage surface. 170 81

We investigated the effects of IL-1, IL-2, IL-6, interferon-gamma and tumour necrosis factor-alpha on growth and cAMP generation of FRTL-5 cells. IL-1 produced a significant stimulation of [3H]thymidine incorporation into FRTL-5 cells without TSH, whereas IL-1 caused significant reductions in [3H]thymidine incorporation induced by TSH or forskolin, which is known as an adenylate cyclase activator. Intracellular cAMP generation of FRTL-5 cells was stimulated by IL-1, whereas TSH-stimulated cAMP generation was inhibited by IL-1. These effects of IL-1 was neutralized by addition of anti-IL-1 antibody. The studies suggested that IL-1 blocks the effects of TSH on proliferation and cAMP generation of FRTL-5 cells on a post-receptor site of TSH.
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PMID:Effects of interleukin 1 on growth and adenosine 3',5'-monophosphate generation of the rat thyroid cell line, FRTL-5 cells. 184 31

Using a functioning rat thyroid cell line (FRTL-5), we examined the effects of some cytokines, particularly interleukin-1 (IL-1) on the growth of thyroid cells. In 5H medium, namely Coon's modified Ham's F-12 medium supplemented with 5% calf serum and a five-hormone preparation consisting of insulin, hydrocortisone, transferrin, glycyl-L-histidyl-L-lysine acetate and somatostatin, IL-1 enhanced the growth of FRTL-5 cells detected by [3H]TdR incorporation. However, in 6H medium (5H medium plus bovine TSH), IL-1 inhibited the growth of FRTL-5 cells. Both effects were neutralized by the addition of anti-IL-1 antibody. Furthermore, IL-1 inhibited the growth of FRTL-5 cells induced by forskolin which is known as an adenylate cyclase activator. FRTL-5 cells have specific IL-1 receptors detected by the binding of 125I-labeled IL-1 alpha. By Scatchard plot analysis, the numbers and the dissociation constants of IL-1 receptors on FRTL-5 cells were shown to be 5225/cell and 8.69 x 10(-10) M. Interleukin-2, interleukin-6 and interferon-gamma (IFN-gamma) had no significant effects on the cell growth in 6H medium, while IFN-gamma and insulin-like growth factor I stimulated cell growth somewhat in 5H medium. These results suggest that IL-1 plays a regulatory role in the growth of thyroid cells through binding to the IL-1 receptors.
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PMID:Inhibitory effect of IL-1 on the TSH dependent growth of rat thyroid cells (FRTL-5). 212 71

The activation of protein kinase C involves its translocation from a cytosol fraction to a membrane fraction. Effects of interferon-gamma (IFN-gamma) on the epidermal protein kinase C were investigated. The treatment of recombinant human IFN-gamma on intact human epidermis resulted in the translocation of protein kinase C from a cytosol to a membrane fraction. The human IFN-gamma had no translocation effect on pig epidermal protein kinase C. Tumor promoter, 12-o-tetradecanoylphorbol-13-acetate (TPA), and a membrane-permeable diacylglycerol analogue, 1-oleoyl-2-acetylglycerol (OAG), both of which are well-known activators of protein kinase C, translocated the epidermal protein kinase C. The IFN-gamma had no direct effect on the epidermal protein kinase C; the addition of the IFN-gamma to partially-purified pig epidermal protein kinase C had no effect on its activity. The effect of the IFN-gamma on human epidermal protein kinase C appears to be through the species specific IFN-gamma receptors. It has been reported that the epidermal beta-adrenergic adenylate cyclase response is decreased following the TPA- (and OAG-) induced activation of protein kinase C. Human recombinant IFN-gamma, however, had no effect on the beta-adrenergic response of the human epidermis. Our results indicate that IFN-gamma affects intact keratinocytes in vitro, resulting in the activation of protein kinase C, which might be related to the physiological effect of IFN-gamma on keratinocyte.
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PMID:Translocation of protein kinase C from cytosol to membrane fractions in human epidermal keratinocytes by recombinant human interferon-gamma. 215 6

Effects of recombinant murine interferon-gamma (rIFN-gamma) on the membrane adenylate cyclase of a murine macrophage cell line (P388D1) were investigated in order to explore the nature of a signal transmitted by IFN-gamma receptor. Following the incubation of P388D1 cells with 40 U/ml of rIFN-gamma, the intracellular level of cAMP gradually increased about twofold over the control level within 60 min, and then began to gradually decline to about half the control level by 24 h incubation. The initial rise in cAMP level appeared to be due to the modest activation of adenylate cyclase and not due to the inhibition of cAMP-phosphodiesterase. Later decrease of intracellular cAMP may be due to quantitative down-regulation of the adenylate cyclase system. The basal enzymatic activity of the membrane prepared from P388D1 cells exposed to IFN-gamma for 24 h was found to be reduced to about 20% of that of the control membrane. However, the quality of the adenylate cyclase system appeared unchanged, because the relative degree of the response of the down-regulated membrane adenylate cyclase to prostaglandin PGE2, NaF, guanylimidodiphosphate (GppNHp), choleara toxin (CT), or forskolin was found to remain unchanged. This quantitative down-regulation of adenylate cyclase must be due to the action of rIFN-gamma, since the prior treatment of rIFN-gamma with either acid (pH 2) or monoclonal anti-IFN-gamma antibody inhibited the ability of IFN-gamma to induce the down-regulation. The rIFN-gamma-induced down-regulation is a reversible process, since the adenylate cyclase activity of the membrane was found to be restored when the rIFN-gamma-exposed cells were cultured for 72 h in the absence of rIFN-gamma. In addition, the 48 h-incubation of P388D1 cells with rIFN-beta or IFN-alpha was found not to significantly affect the membrane adenylate cyclase system.
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PMID:Interferon-gamma down-regulates membrane adenylate cyclase activity of a murine macrophage-like cell line (P388D1). 256 71

The adenylate cyclase activator, forskolin, was found to induce expression of class I and class II major histocompatibility complex antigens in a B precursor cell line, Reh, as well as in a B lymphoid cell line, Raji. No such effect was, however, observed when the promyelocytic cells line HL-60 was treated with either forskolin or the cAMP analogue 8-bromoadenosine cyclic monophosphate. As expected, all three cell lines showed reduced proliferation upon forskolin treatment. Forskolin induced expression of class I and class II major histocompatibility complex antigens in cell lines not affected by interferon-gamma and vice versa, indicating that cAMP is not involved in the regulation of histocompatibility antigens by interferon-gamma. We also compared the effect of interferon-gamma and 12-O-tetradecanoylphorbol 13-acetate on major histocompatibility complex class I and class II expression, and despite differences in the response on the tested cell lines, we can not at this point exclude the possibility that protein kinase C is involved in the action of interferon-gamma.
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PMID:Distinct effect of forskolin and interferon-gamma on cell proliferation and regulation of histocompatibility antigen expression in hematopoietic cells. 308 31

We related the effects of c-myc expression on the ability of growth inhibitors to block the cells in the G0/G1 phase of the cell cycle. In two different B-cell lines, there was an association between the accumulation of cells in the middle to late G1 phase of the cell cycle and a rapid transient downregulation of c-myc mRNA levels. The phorbol ester TPA and the adenylate cyclase activator forskolin reduced the c-myc RNA, levels and after 3 days of treatment a proportion of the cells accumulated in G1. In contrast, neither interferon-gamma, tumor necrosis factor-alpha nor the monoclonal antibody 33-1 against DQ major histocompatibility antigens changed the cell-cycle distribution or regulated the c-myc RNA levels. Yet, all five growth inhibitors reduced the proliferation to approximately the same extent. The growth reduction was not accompanied by definite differentiation, as judged by the absence of the B-cell differentiation marker B1 (CD20).
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PMID:Downregulation of c-myc RNA is not a prerequisite for reduced cell proliferation, but is associated with G1 arrest in B-lymphoid cell lines. 311 97

The effect of prostaglandin (PG) E2 on macrophage activation by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) was evaluated. Murine macrophages infected with Leishmania enriettii or Leishmania major were activated by exposure to IFN-gamma (10-50 U/ml) and TNF-alpha (30-3000 U/ml), leading to intracellular parasite destruction within 24-48 h. Leishmanicidal activity was markedly increased when activation was performed in the presence of PGE2 (10(-9)-10(-7) M) or arachidonate (10(-5) M, a PG precursor), concomitant with enhanced nitrite release and glucose oxidation through the hexose monophosphate shunt pathway. Conversely, activation was reduced by indomethacin and hydrocortisone, two inhibitors of PG synthesis. Parasite killing and nitrite production were fully restored by exogenous PGE2, indicating that inhibition by these drugs was related to their ability to block PG production. PG can stimulate adenylate cyclase, thus raising intracellular cAMP levels. Accordingly, dibutyryl-cAMP, theophylline (which prevents cAMP breakdown), and forskolin (an activator of adenylate cyclase) all stimulated macrophage activation. Finally, PGE2 and cAMP enhanced expression of inducible nitric oxide synthase mRNA in response to IFN-gamma and TNF-alpha, and this effect was inhibited by the cAMP antagonist 2'-O-methyl adenosine. These findings are consistent with the hypothesis that PGE2 acts as a positive agonist in macrophage activation by IFN-gamma and TNF-alpha via its capacity to modulate intracellular cAMP levels.
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PMID:Effect of PGE2 and of agents that raise cAMP levels on macrophage activation induced by IFN-gamma and TNF-alpha. 754 22

The aim of the present study was to determine whether two classical macrophage activators, bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) could affect the accumulation of the second messenger cAMP in cultured rat microglia and astrocytes. Purified microglia and astrocyte secondary cultures obtained from the neonatal rat were grown for 3 days in basal medium Eagle (BME) + 10% fetal calf serum (FCS). Exposure of microglia to LPS resulted into a dose- and time-dependent decrease in the accumulation of cAMP induced by receptor-mediated (isoproterenol or prostaglandin E2) or direct (forskolin) activation of adenylate cyclase. The inhibitory effect of LPS was rapid (a 10 min preincubation was sufficient to approach a maximal effect), occurred at low doses (IC50 = 1.2 ng/ml), and was not abrogated by pertussis toxin. A selective inhibitor of type IV phosphodiesterase (rolipram, 100 nM) prevented the effect of LPS on cAMP accumulation, while inhibitors of other forms of phosphodiesterase were unable to do so. IFN-gamma (100 u/ml) also caused a depression of the evoked cAMP accumulation in microglia after a 10 min preincubation, and its effect was prevented by rolipram, as in the case of LPS. Astrocytes differed from microglia in that LPS (1-100 ng/ml) did not inhibit the accumulation of cAMP induced by either isoproterenol or forskolin; on the other hand, IFN-gamma did have an inhibitory effect (though less pronounced than in microglia) that could be prevented by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma and lipopolysaccharide reduce cAMP responses in cultured glial cells: reversal by a type IV phosphodiesterase inhibitor. 755 45

To elucidate the regulation mechanism of adrenomedullin (AM) production in blood vessels, we examined the effects of 30 substances on AM production in cultured rat vascular smooth muscle cells (VSMCs). Forskolin and 8-bromo-cAMP suppressed production and gene transcription of AM. Since VSMC expresses AM receptors coupled with adenylate cyclase, AM production may be regulated by intracellular cAMP concentration. Thrombin, vasoactive intestinal polypeptide and interferon-gamma also inhibited AM production, while angiotensin II, endothelin-1, bradykinin, substance P, adrenaline, phorbol ester and fetal calf serum stimulated AM production in VSMC. These results suggest that AM production is regulated by a variety of substances, indicating complex systems regulating AM production.
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PMID:Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. 764 78


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