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)

Lymphocytes have surface receptors for a variety of hormones that play an important part in modulating the immune response. Most previous studies, however, have examined the effects of hormone agonists on heterogeneous bulk populations of cells, making it difficult to precisely identify the responding target cells. We have therefore studied a set of well characterized T cell clones for a series of adenylate cyclase-linked hormone receptors and examined changes in receptor expression that occur after cell activation. All clones tested had receptors for histamine, isoproterenol, and PGE1, but not for several other cAMP-active hormone agonists. The apparent receptor affinities and their specificities were characteristic of typical histamine H2, beta 2-adrenergic, and PGE receptors. The cAMP response to PG was higher and longer lasting than that to histamine or isoproterenol, both of which appear to undergo receptor desensitization. After activation of quiescent cells in IL-2-containing media, the cAMP response to all three ligands increased, peaking 4 to 5 days after stimulation, and then returned to basal levels as the cells ceased proliferating. Inasmuch as this effect did not require Ag, it appears that the coordinate regulation of responsiveness to these ligands is a direct result of lymphocyte activation. This increase in hormone receptor activity is functionally analogous to the up-regulation of receptors for other ligands that occurs after lymphocyte activation and further demonstrates the important immunoregulatory role played by the changing repertoire of surface receptors that is associated with activation.
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PMID:Hormone receptors on cloned T lymphocytes. Increased responsiveness to histamine, prostaglandins, and beta-adrenergic agents as a late stage event in T cell activation. 289 15

Forskolin (FK), a reversible activator of adenylate cyclase, markedly enhanced the expression of interleukin-2 receptor (IL-2-R) on a human natural killer (NK)-like cell line, YT. The FK-induced increase in IL-2-R on YT cells closely correlated with an increase in intracellular cyclic AMP (cAMP) level, and was mimicked by dibutyryl cyclic AMP (dbcAMP). FK induced both high and low affinity IL-2-R on the cells. Using a cDNA for the IL-2-R as a probe, the FK-induced IL-2-R expression was shown to be associated with an increase in IL-2-R mRNA. FK also enhanced the IL-2-R expression on a human T lymphotrophic virus I (HTLV-I) positive T-cell line (YTA-1H) and augmented the phorbol ester-induced expression of IL-2-R on HTLV-I negative T-cell lines (HSB-2 and HPB-ALL). These results suggest the possibility that the stimulation of adenylate cyclase may serve as a pathway leading to activation of the IL-2-R gene in certain types of lymphocytes.
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PMID:Activation of interleukin-2 receptor gene by forskolin and cyclic AMP analogues. 303 78

Regulation of lymphocyte responses to activation of the CD3/TCR complex by other cell surface proteins expressed on lymphocytes is a well established phenomenon. CD44 is an example of such a cell surface protein. Anti-CD44 mAb have been identified which either stimulate or inhibit lymphocyte function. Certain anti-CD44 mAb augment proliferation and IL-2 production by T cells stimulated through the CD2 or CD3/TCR pathways. An anti-CD44 mAb with opposing properties has also been identified. This mAb inhibits activation of human T cells by preventing the rise in [Ca2+]i stimulated by OKT3. The purpose of experiments reported here was to further characterize this phenomenon. The results show that the anti-CD44 mAb, 212.3, does not inhibit inositol phosphate turnover stimulated by OKT3 but does inhibit elevation of intracellular [Ca2+]i in these same cells. Addition of 212.3 to purified human T cells results in a rapid increase in intracellular levels of cAMP. Elevation of cAMP by 212.3 is time- and concentration-dependent. Activation of adenylate cyclase by forskolin also results in elevation of intracellular cAMP and inhibition of the increase in [Ca2+]i stimulated by OKT3. Taken together, these data suggest that CD44 may be positively coupled to adenylate cyclase and that activation of adenylate cyclase by the anti-CD44 mAb, 212.3, may mediate the inhibition of the OKT3-stimulated elevation of [Ca2+]i.
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PMID:Elevation of intracellular cAMP in human T lymphocytes by an anti-CD44 mAb. 750 12

We have investigated the role of prostaglandin E2 (PGE2) in the regulation of cytokine release (IL-2, IL-3 and IFN) by cortico-resistant thymocytes (CRT) stimulated or not through the T-cell antigen receptor by an anti-CD3 monoclonal antibody (mAb). CRT were found to spontaneously produce IL-2 and IL-3 on day 4 of culture, but not IFN. After activation with an anti-CD3 mAb, the maximal levels for IL-2 and IFN were observed on day 1 and for IL-3 on day 4. Addition of PGE2 inhibits IL-2 production and has no effect on IFN production. Indomethacin, an inhibitor of the cyclooxygenase pathway, enhanced both IL-2 and IFN production. In contrast, IL-3 secretion by anti-CD3 activated CRT was up-regulated by PGE2, and its level was decreased in the presence of indomethacin in both stimulated or unstimulated cells. As has been observed with PGE2, forskolin which activates adenylate cyclase increases the IL-3 level. Thus PGE2 may interfere in the process of thymocyte proliferation and/or differentiation by regulating differentially the interleukin production.
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PMID:Regulation by PGE2 of IL-2, IL-3 and IFN production by cortico-resistant thymocytes. 751 Feb 66

Prostaglandin E2 (PGE2) inhibits Ig production by adult B cells stimulated with Staphylococcus aureus and IL-2, and inhibits the production of IL-2 by anti-CD3 stimulated T cells. By contrast, PGE2 did not inhibit T cell-dependent Ig production by adult B cells. However, T cell-dependent Ig secretion by neonatal B cells was markedly inhibited by PGE2 even in the presence of supplemental IL-2. Forskolin, a direct activator of adenylate cyclase, and dibutyryl cAMP caused similar effects. PGE2 inhibited T cell-dependent Ig secretion by both neonatal CD5+ and CD5- B cells but did not inhibit Ig secretion by either CD5+ or CD5- adult peripheral blood B cells. PGE2 did not inhibit IL-2-dependent anti-CD3 stimulated neonatal T cell proliferation or T cell-dependent neonatal B cell proliferation. PGE2 inhibited neonatal B cell Ig production when addition was delayed, suggesting that initial B cell activation and proliferation were not blocked, but that PGE2 prevented subsequent differentiation. In addition, PGE2 inhibited neonatal T cell help independent of cytokine production. PGE2-induced cAMP levels in neonatal B and T cells were not different from adult levels. These results indicate that production of Ig by neonatal lymphocytes is uniquely sensitive to the inhibitory effects of agents such as PGE2 that elevate cAMP levels. This sensitivity may contribute to the suppressed in vivo responses of human neonatal B cells.
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PMID:Prostaglandin E2 inhibits T cell-dependent Ig secretion by neonatal but not adult lymphocytes. 751 34

Elevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a beta 2-agonist which activates adenylate cyclase, its ability to inhibit cytokine production was evaluated. Though salmeterol, and the related drug albuterol, did not inhibit IL-1 beta production in vitro, both drugs did inhibit tumour necrosis factor-alpha (TNF-alpha) secretion by lipopolysaccharide (LPS)-activated THP-1 cells with similar IC50s of approximately 0.1 microM. This inhibition was effectively reversed by the beta 2-antagonist oxprenolol, indicating that the inhibition was mediated through the beta 2-adrenergic receptor. A strikingly different reactivity profile was seen with T cells. Salmeterol was able to inhibit the activation of both mouse and human T cells, as measured by proliferation and IL-2 secretion in response to anti-CD3 antibody, whereas albuterol was completely inactive in these assays. This T cell inhibition by salmeterol was about 10-fold less potent than that for TNF-alpha production, and was not reversed by a beta 2-antagonist, indicating that a different mechanism was involved in the effect of salmeterol on T cells. Paralleling the TNF-alpha inhibitory activity in vitro, oral dosing of salmeterol and albuterol inhibited LPS-induced increase in murine serum TNF level in vivo, with ED50s of approximately 0.1 mg/kg. This inhibition could be abrogated by dosing orally with the beta-blocker propranolol. The long-acting pharmacological profile of salmeterol was apparent in that it maintained its efficacy for 3 h, while albuterol had a much shorter duration of action. Salmeterol also had some protective effects in the galactosamine/LPS model of endotoxic shock, which is dependent upon TNF-alpha production. Though salmeterol inhibited serum TNF-alpha levels by up to 94% in this assay, it protected less than 50% of the animals from the lethal effects of the LPS/galactosamine mixture. This observation suggests that functional levels of TNF-alpha localized in tissues may not be accurately reflected by serum levels.
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PMID:Anti-inflammatory activity of salmeterol: down-regulation of cytokine production. 788 70

The serotonin (5HT1A) receptor subtype is one member of the 5HT1 receptor family and is constitutively expressed on Jurkat cells and is elevated on human T lymphocytes after mitogenic activation. Published reports show that human T lymphocytes and monocytes also release 5HT after stimulation with PHA or IFN-gamma. In lymphocytes and the central nervous system, the 5HT1A receptor is coupled to regulation of adenylate cyclase. The 5HT1A receptor agonists inhibit activation of adenylate cyclase. The purpose of the experiments reported here was to investigate further the role 5HT and the 5HT1A receptor may play in the regulation of human and murine T cell activity. For this purpose, human PBMC or murine spleen cells were used for experimental purposes rather than Jurkat cells. The results show that inhibition of 5HT synthesis inhibits IL-2-stimulated human T cell proliferation and that addition of 5-hydroxytryptophan, a precursor of 5HT, reverses inhibition of T cell proliferation. The 5HT1 receptor antagonist, metitepine, and the 5HT1A selective antagonist, pindobind-5HT1A, also block T cell proliferation. Inhibition by metitepine is reversed by 5HT and by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) (8-OH-DPAT). Selective 5HT1A receptor antagonists cause elevation of cAMP in human T cells. In a murine model, selective 5HT1A receptor antagonists inhibit contact sensitivity responses but not Ab responses to oxazalone in vivo. Inhibition is reversed by 8-OH-DPAT. In addition, production of Th1 cytokines, such as IL-2 and IFN-gamma, by Ag-stimulated, immune murine spleen cells is inhibited by 5HT1A receptor antagonists in vitro but not by 5HT1C/2 receptor antagonists.
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PMID:Inhibitors of serotonin synthesis and antagonists of serotonin 1A receptors inhibit T lymphocyte function in vitro and cell-mediated immunity in vivo. 802 90

T lymphocyte stimulation via the Ag receptor results in activation of phospholipase C gamma 1 that catalyses the hydrolysis of phosphatidylinositol (PI). The hydrolysis generates inositol phosphate and diacylglycerol, which in turn, increase intracellular Ca2+ concentration and activates protein kinase C, respectively. Agonists operating via the adenylate cyclase pathway or cell permeable cAMP analogues inhibit T cell activation by interfering with the PI-turnover. We have shown that dbcAMP inhibits PI-independent mitogenic signals in T cells after stimulation with TPA plus ionomycin. dbcAMP inhibited the TPA plus ionomycin-induced transcription of IL-2 and IL-2R genes in EL4 cells, suggesting interference with biochemic events downstream to PI hydrolysis and upstream to transcription of early activation genes. Because many of the early genes operating in T cell mitogenesis possess a TPA-response element (TRE) in their promoter region, we tested the effect of cAMP on the TRE-binding protein, TPA-response element (TRE) in their promoter region, we tested the effect of cAMP on the TRE-binding protein, AP-1. dbcAMP increased the binding activity of nuclear proteins consisting of Fos:Jun heterodimers to a TRE-containing oligonucleotide, but altered the composition of Jun proteins in the AP-1. Furthermore, the TPA plus ionomycin-induced transcription program of members of the jun and fos family of genes was altered by dbcAMP, suggesting that inhibition of T cell proliferation by dbcAMP is a consequence of intervention in transcriptional regulation by TRE-binding proteins.
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PMID:Cyclic AMP inhibits phosphatidylinositol-coupled and -uncoupled mitogenic signals in T lymphocytes. Evidence that cAMP alters PKC-induced transcription regulation of members of the jun and fos family of genes. 814 23

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

Although cholera toxin B subunit is a potent mucosal immunogen in vivo, its predominant effect in vitro is inhibition of T cell and B cell activation. We reported earlier that this inhibition was not mediated through activation of adenylate cyclase and increases in intracellular cAMP. There is increasing evidence that T cell activation is initiated through the phosphatidyl inositol second messenger system in which phosphatidyl inositol bisphosphate is hydrolyzed by phospholipase C, producing inositol trisphosphate (IP3) and diacylglycerol. IP3 increases cytosolic calcium and diacylglycerol binds, translocates, and activates protein kinase C (PKC). These signals lead to a complex series of events eventuating in activation of a number of genes important in cell proliferation. In this study, we asked whether the mechanism of T cell inhibition by B subunit of cholera toxin (CT-B) was due to interference with the phosphatidyl inositol second messenger system. We found that substitution of ionomycin and PMA for IP3 and diacylglycerol, respectively, in culture induced T cell proliferation but only if both were present simultaneously. Such proliferation was inhibited by CT-B even if added hours after the start of culture. An assay for cytosolic PKC activity demonstrated that PMA translocation of PKC from cytosol to membrane was not inhibited by CT-B, indicating that CT-B does not inhibit activation of PKC. There was no inhibition of Con A-stimulated T cell phosphoinositol turnover. Moreover, Con A added to Fura-2 AM-loaded cells caused a rapid rise in cytosolic calcium, which CT-B preincubation did not alter. These results indicate that CT-B did not inhibit IP3 generation or action. We next looked at expression of genes involved in T cell proliferation. CT-B inhibited the production of IL-2 by mitogen-activated T cells; Northern analysis showed that this inhibition was associated with decreased levels of IL-2 mRNA. Expression of IL-2R and of transferrin receptors was only modestly reduced. Despite the presence of IL-2R on the T cells exposed to CT-B, the addition of exogenous IL-2 to the cultures did not reverse the CT-B-induced T cell inhibition. We conclude that the T cell inhibition by CT-B is not mediated by interference with the activation of the phosphatidylinositol second messenger system but occurs at a later stage of T cell activation.
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PMID:Inhibition of murine T cell activation by cholera toxin B subunit is not mediated through the phosphatidylinositol second messenger system. 846 69


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