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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PGE2 is known to inhibit IL-2 and IFN-gamma production from Th cells and is widely viewed as a general immunosuppressant. However, PGE2 was found not to inhibit IL-4 production from Th2 clones, and IL-5 production from these clones was slightly enhanced. The same results were obtained with short term T cell lines, which indicates that the lack of inhibition of IL-4 and IL-5 production by PGE2 is a general phenomenon. PGE2 functions by increasing cAMP levels through activation of adenylate cyclase. Despite its failure to inhibit lymphokine release, PGE2 was capable of increasing cAMP levels in Th2 cells, and forskolin, a direct activator of adenylate cyclase, also did not inhibit IL-4 or IL-5 production. These data indicate that the failure of PGE2 to inhibit IL-4 and IL-5 production was not due to an inability of PGE2 to induce an increase in intracellular cAMP, and suggested instead that the expression of IL-4 and IL-5 in Th2 cells is insensitive to elevated cAMP levels. When Th0 clones were examined, PGE2 was again found to differentially affect IL-2 and IL-4 production in three of five clones tested. In two additional Th0 clones, both IL-2 and IL-4 production were inhibited. These data suggest that lymphokine production may be regulated on two different levels. First, Th1- and Th2-associated lymphokines may be differentially sensitive to intracellular signals such as cAMP. Second, T cell subsets may exist, including subsets of Th0 cells, with different signaling pathways. In addition, our data suggest that PGE2 may play an important role in regulating the development of a response dominated by Th1- or Th2-associated lymphokines.
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PMID:Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. 184 2

We have investigated the signal transduction pathways mediated by IL-1 in the Th 2 cell line D10.A, and we have made the following findings. Interaction of IL-1 with its receptor leads to the translocation of protein kinase C (PKC) from the cytosol to the membrane, phosphorylation of the 80-kDa protein that is substrate for PKC, as well as an increase in the level of cAMP. In addition, IL-1 induced IL-5 mRNA expression in these cells. We have established that the IL-5 gene is activated in D10.A cells in response to either phorbol esters or 8-Br cAMP, and that the two agents act as cofactors. IL-1 is able to synergize with phorbol esters and is additive with 8-Br cAMP for IL-5 mRNA expression. There are two possibilities to explain these results: 1) D10.A cells express two types of functional IL-1R, each linked to an independent signal transduction pathway; or 2) these cells have only one kind of IL-1R which, upon ligand interaction, mediates the activation of both the PKC and the adenylate cyclase pathway.
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PMID:IL-1 activates two separate signal transduction pathways in T helper type II cells. 215 78

Effects of prostaglandin E2 (PGE2) on murine B-cell activation induced by two distinct B-cell differentiation factors, B151-TRF1/IL-5 and B151-TRF2, were examined. A final differentiation of unprimed B cells into IgM-producing cells induced by B151-TRF2 was markedly inhibited by PGE2 at physiological concentrations (around 10(-8) M), whereas B151-TRF1/IL-5- induced antibody responses of unprimed as well as activated B cells were not affected by PGE2, even at 10(-6) M. B-cell responses induced by B151-TRF2-like factors from autoimmune-prone MRL/lpr mice were also inhibited by PGE2. Biphasic increases in intracellular cyclic AMP (cAMP) levels were induced by culturing B cells with 10(-6) or 10(-8) M PGE2: rapid increases within 8 min and delayed increases around 16 hr. The direct addition of dibutyryl cAMP to cultures of B cells resulted in marked inhibition of antibody responses when stimulated with B151-TRF2 but not with B151-TRF1/IL-5. The B151-TRF2-induced antibody responses were also inhibited by cAMP-elevating reagents such as forskolin, cholera toxin and theophylline. Furthermore, 2'.5'-dideoxyadenosine, which is an inhibitor of adenylate cyclase, prevented the PGE2-mediated cAMP accumulation in unprimed B cells as well as the PGE2-mediated inhibition of B151-TRF2-induced B-cell responses when added at the initiation of culture. These results suggest that PGE2 inhibits B151-TRF2-induced antibody responses through the activation of adenylate cyclase and subsequent accumulation of intracellular cAMP, whereas B151-TRF1/IL-5-responsive B cells are resistant to the inhibitory effect of PGE2 and cAMP.
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PMID:Different effect of prostaglandin E2 on B-cell activation by two distinct B-cell differentiation factors, B151-TRF1/IL-5 and B151-TRF2: selective inhibition of B151-TRF2-induced antibody response through increases in intracellular cyclic AMP levels. 255 85

The signaling mechanisms that regulate lymphokine gene expression in the murine Th2 clone D10.G4.1 were investigated by comparing the steady state mRNA levels of six lymphokine genes in response to cellular treatment with various activators and inhibitors of several key signaling pathways. A surprising degree of differential regulation was found. All of the genes studied (IL-3, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage (GM)-CSF) were induced by the lectin Con A and the TCR idiotype-specific mAb 3D3. However, the induction of the IL-3, IL-4, and GM-CSF genes, but not the IL-5, IL-6, and IL-10 genes, was strongly inhibited by cyclosporin A. Furthermore, IL-5, IL-6, and IL-10 genes were independently induced by IL-1 alpha, the phorbol ester PMA, and by forskolin, an activator of adenylate cyclase. Results of studies performed with use of the Ca2+ ionophore A23187 indicated that elevation of intracellular Ca2+ levels is sufficient to fully induce IL-3 and IL-4 gene expression. Protein kinase C activation was also required for full induction of the GM-CSF gene and seemed to be obligatory for maximal IL-5 gene expression. The patterns of mRNA induction by the different stimuli broadly correlated with increased rates of transcription. In addition to their induction by IL-1 alpha, the IL-5, IL-6, and IL-10 genes were also induced by mAbs to CD2 and to CD45. In contrast, adding CD45 mAb strongly inhibited the induction of IL-3, IL-4, and GM-CSF genes through TCR stimulation. These results indicate that distinct groups of lymphokine genes may be differentially regulated by signaling pathways that are activated by stimulation of the TCR and other cell surface molecules.
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PMID:TCR-dependent and -independent signaling mechanisms differentially regulate lymphokine gene expression in the murine T helper clone D10.G4.1. 791 89

PGE2 is a well known immunomodulator that has multiple effects on the immune system. We demonstrate that PGE2 selectively and dose dependently inhibits IL-2 and IFN-gamma production by mitogenically stimulated human PBL and CD4+ TLC, although at low concentrations IL-4 production is not affected and IL-5 production is even up-regulated. In the tested TLC, PGE2 induced a dramatic elevation (up to 85-fold) of the intracellular cAMP levels. The action of PGE2 may, therefore, be associated with elevation of intracellular cAMP levels, affecting IL-4 and IL-5 differentially from IL-2 and IFN-gamma production. To test this hypothesis we investigated cytokine production by TLC in the absence or presence of agents that affect cAMP levels, either directly (2'-O-dibutyrylcAMP) or through activation of adenylate cyclase (forskolin) or by blocking of phosphodiesterase (3-isobutyl-1-methyl-xanthine). Similar to PGE2, forskolin, 2'-O-dibutyrylcAMP, and 3-isobutyl-1-methyl-xanthine induced inhibition of IL-2 production by TLC and up-regulation of IL-5 production. However, in contrast to PGE2, these agents suppressed IL-4 production although IFN-gamma production was only moderately affected. No significant differences were found between intracellular cAMP levels of mitogenically stimulated Th1 cell clones, which predominantly secrete IL-2 and IFN-gamma, and those of Th2 cell clones, which mainly secrete IL-4 and IL-5. Our results indicate that PGE2 selectively modulates cytokine secretion profiles of human T cells and that elevation of cAMP levels has an important, but possibly not exclusive, regulatory role in this phenomenon.
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PMID:Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. 839 May 34

The effects of cAMP-elevating agents on antigen-induced IL-5 (interleukin-5) messenger RNA expression and protein production were examined in vitro in an antigen-driven system of splenocytes from ovalbumin sensitized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 10(-5) M) and by dibutyryl-cAMP (db-cAMP) (3 x 10(-4) M), but not by the type 3 and type 5 PDE inhibitors milrinone and zaprinast (10(-5) M), respectively. Forskolin (10(-5) M), an adenylate cyclase activator, was noninhibitory alone but potentiated inhibition by rolipram. Inhibition was associated with a decrease in IL-5 mRNA expression. Cycloheximide 10(-6) M and actinomycin 2 micrograms/ml abolished IL-5 production and mRNA expression. We conclude that in splenocytes from sensitized mice, IL-5 production and mRNA expression depend on antigen stimulation. The time course of IL-5 protein production is closely related to IL-5 mRNA expression and depends on de novo protein synthesis. db-cAMP and a selective PDE4 inhibitor, alone or in combination with forskolin, are the only cAMP-elevating agents that dose-dependently inhibited antigen-induced IL-5 mRNA expression and protein production. These results are in agreement with in vivo inhibition by a selective PDE4 inhibitor of antigen-induced pulmonary eosinophil infiltration and IL-5 production in sensitized mice, and they suggest that PDE4 inhibitors have potential for treating respiratory allergy.
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PMID:In vitro down-regulation of antigen-induced IL-5 gene expression and protein production by cAMP-specific phosphodiesterase type 4 inhibitor. 881 36

A characteristic feature of apoptosis is that the cellular contents that are biologically active are always surrounded by the cell membrane throughout the entire process. Thus the apoptotic cells are eliminated calmly and quickly without evoking inflammation. In allergic inflammation activated eosinophils and lymphocytes have been known to accumulate at the site of inflammation at least in part because of their prolonged survival. Corticosteroids are the most potent anti-inflammatory agent used for treating asthma. They inhibit the prolonged survival of eosinophils and lymphocytes directly by inducing apoptosis and indirectly by suppressing the release of cytokines supporting their survival. Theophylline, a classical bronchodilator, has been reported to have anti-inflammatory effects. Surprisingly, theophylline inhibited the prolonged survival of eosinophils in the presence of IL-5 in vitro by means of induction of apoptosis. Lymphocytes also undergo apoptosis in the presence of theophylline. One of the mechanisms for theophylline to induce apoptosis in eosinophils and lymphocytes is to elevate intracellular cyclic adenosine monophosphate because phosphodiesterase inhibitors and adenylate cyclase activators, which increase intracellular cyclic adenosine monophosphate, can cause apoptosis in those cells. Induction of apoptosis is beneficial in allergic inflammation, and the use of corticosteroids and theophylline in combination may be appropriate to induce apoptosis in eosinophils and lymphocytes.
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PMID:Apoptosis of eosinophils and lymphocytes in allergic inflammation. 1040 Aug 33

CCR-3 is a major receptor involved in regulating eosinophil trafficking. Initial analysis of chemokine receptors has demonstrated unique receptor events in different cell types, indicating the importance of investigating CCR-3 events in eosinophilic cell lines. We now report that the eosinophilic cell line, acute myelogenous leukemia (AML) 14.3D10, expresses eosinophil granule proteins and eotaxin, but has no detectable expression of eosinophil chemokine receptors. Treatment of the cell line with butyric acid and IL-5 results in a dose-dependent synergistic induction of CCR-3 and, to a lesser extent, CCR-1 and CCR-5. Interestingly, using a luciferase reporter construct under the control of the hCCR-3 promoter, the uninduced and induced cells display high, but comparable, levels of promoter activity. Differentiated AML cells developed enhanced functional activation, as indicated by adhesion to respiratory epithelial cells and chemokine-induced transepithelial migration. Chemokine signaling did not inhibit adenylate cyclase activity even though calcium transients were blocked by pertussis toxin. Additionally, chemokine-induced calcium transients were inhibited by pretreatment with PMA, but not forskolin. Eotaxin treatment of differentiated AML cells resulted in marked down-modulation of CCR-3 expression for at least 18 h. Receptor internalization was not dependent upon chronic ligand exposure and was not accompanied by receptor degradation. Thus, CCR-3 is a late differentiation marker on AML cells and uses a signal transduction pathway involving rapid and prolonged receptor internalization, calcium transients inhibitable by protein kinase C but not protein kinase A, and the paradoxical lack of inhibition of adenylate cyclase activity.
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PMID:Molecular analysis of CCR-3 events in eosinophilic cells. 1062 56

Gangliosides are sialic acid-containing glycolipids. We studied the in vitro effects of gangliosides on Th1 and Th2 cytokine production in PHA-stimulated human T cells. Gangliosides GD1b, GT1b, and GQ1b (each 100 nM) enhanced PHA-induced IL-2 secretion of peripheral blood T cells approximately 4-fold and enhanced that of IFN-gamma 3- to 4-fold compared with controls. These gangliosides decreased PHA-induced IL-4 secretion by 50-53% and that of IL-5 by 53-63% compared with controls, respectively. The other gangliosides did not alter the secretion of Th1 or Th2 cytokines. RT-PCR showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-gamma transcription and suppressed that of IL-4 and IL-5. Transient transfection assays of Jurkat T cells showed that GD1b, GT1b, and GQ1b enhanced PHA-induced IL-2 and IFN-gamma promoter activities but suppressed those of IL-4 and IL-5. The cAMP analogue dibutyryl cAMP and the cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine each reversed GD1b-, GT1b-, and GQ1b-induced stimulation of IL-2 and IFN-gamma production and inhibition of IL-4 and IL-5 production at the levels of proteins, transcription, and promoter activities. GD1b, GT1b, and GQ1b suppressed PHA-induced increase in cAMP level in T cells. These gangliosides suppressed PHA-stimulated adenylate cyclase activity in T cells. These results suggest that GD1b, GT1b, and GQ1b may enhance Th1 cytokine production while suppressing Th2 production by inhibiting adenylate cyclase activity.
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PMID:Gangliosides GD1b, GT1b, and GQ1b enhance IL-2 and IFN-gamma production and suppress IL-4 and IL-5 production in phytohemagglutinin-stimulated human T cells. 1112 78

It is reported that anti-mycotic agents are effective for the treatment of patients with atopic dermatitis. We studied the in vitro effects of anti-mycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from atopic dermatitis patients and normal donors. The amounts of interleukin-4 and interleukin-5 secreted by anti-CD3/CD28-stimulated T cells were higher in atopic dermatitis patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole, and nonazole terbinafine hydrochloride, and tolnaftate reduced interleukin-4 and interleukin-5 secretion without altering that of interferon-gamma and interleukin-2 in anti-CD3/CD28-stimulated T cells from both atopic dermatitis patients and normal donors. The azole derivatives were more inhibitory than nonazole anti-mycotics. These anti-mycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for interleukin-4 and interleukin-5. The 3',5'-cyclic adenosine monophosphate analog dibutyryl 3',5'-cyclic adenosine monophosphate reversed the inhibitory effects of the anti-mycotics on interleukin-4 and interleukin-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular 3',5'-cyclic adenosine monophosphate in T cells, and the increase was greater in atopic dermatitis patients than in normal donors. The increase of 3',5'-cyclic adenosine monophosphate by anti-CD3/CD28 correlated with interleukin-4 and interleukin-5 secretion by anti-CD3/CD28. The transient 3',5'-cyclic adenosine monophosphate increase was suppressed by anti-mycotics, and azole derivatives were more suppressive than nonazoles. Azole derivatives inhibited the activity of cyclic adenosine monophosphate-synthesizing adenylate cyclase whereas terbinafine hydrochloride and tolnaftate enhanced the activity of 3',5'-cyclic adenosine monophosphate-hydrolyzing cyclic nucleotide phosphodiesterase in atopic dermatitis and normal T cells. These results suggest that the anti-mycotics may suppress interleukin-4 and interleukin-5 production by reducing 3',5'-cyclic adenosine monophosphate signal, and stress their potential use for the suppression of T helper-2-mediated allergic reactions.
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PMID:Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. 1188 33


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