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)

The objective of the present studies was to determine whether the existence of functional glucagon receptors could be established on lympoid cells. The glucagon receptor, which positively regulates adenylate cyclase, is a member of the superfamily of seven transmembrane domain G-protein coupled receptors. Previously reported specific binding with [125I]-glucagon to a variety of lymphoid and myeloid cell preparations suggests that glucagon receptors are expressed within the immune system. In the present study, Northern analysis of polyA RNA isolated from primary mouse and rat derived lymphoid tissues and lymphoid cell lines EL-4.IL-2, Jurkat E6-1, CH12LX, and BCL1-3B3 cells were probed with a 32P-labeled human hepatic glucagon receptor. Mouse spleen and thymus, rat spleen, and the B cell line, CH12LX, all possessed a single 1.5 kb fragment (BCL1-3B3, 1.4 kb) which hybridized to the glucagon receptor cDNA probe, as compared to mouse liver which exhibited a 2.8 kb fragment. EL-4.IL-2 and Jurkat E6-1 cells possessed a 3.7 kb fragment with an additional 2.75 kb band present in Jurkat E6-1 cells. Treatment of mouse splenocytes and T- and B-lymphoma cells with glucagon (0 - 100 nM) produced a dose-dependent enhancement in intracellular cAMP which was maximal at 5 min post treatment followed by a gradual decline. Direct addition of glucagon to spleen cell cultures over a broad concentration range produced no effect on either lymphoproliferation following stimulation with anti-CD3 mAb, or LPS nor on the antibody forming cell (AFC) response to sRBC. Conversely, glucagon effectively reversed the suppression of the sRBC AFC response produced by delta9-tetrahydocannabinol (delta9-THC), and partially reversed the suppression produced by 2',3'-dideoxyadenosine, both of which are potent inhibitors of adenylate cyclase. These studies confirm the expression of functional glucagon receptors on lymphoid cells.
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PMID:Expression of functional glucagon receptors on lymphoid cells. 863 21

Humoral and cellular immune responses were analysed in mice inoculated intranasally with Bordetella bronchiseptica. After infection, the number of bacteria that colonized the respiratory tract of the mice increased during the first day and decreased thereafter. Total IgG levels increased as early as 14 days after infection and decreased with time after infection, whereas total IgA and IgM levels were lower but remained stable. Specific antibodies to the bacteria were mainly IgG2a and IgA and persisted up to 10 months after infection. Some of these specific antibodies were directed against adenylate cyclase-haemolysin, the bacterial factor that had been shown to be necessary for initiation of infection. The proliferation of Bordetella bronchiseptica-reactive spleen cells occurred during the acute phase of infection. T cells from infected mice produced increasing amounts of IFN gamma and IL-2 after infection. Although very low levels of IL-10 were produced, no IL-4 was detected after bacterial stimulation in vitro. These results suggest that Bordetella bronchiseptica infection induces primarily a Th1-type T-cell response. Importantly, the authors demonstrated that antibody and T-cell responses directed against bacterial determinants of the virulent strain and to purified adenylate cyclase-haemolysin were long-lasting. This observation could be due to the fact that Bordetella bronchiseptica may persist intracellularly in the host as it was demonstrated in vitro.
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PMID:Intranasal inoculation of Bordetella bronchiseptica in mice induces long-lasting antibody and T-cell mediated immune responses. 863 98

Our previous studies have shown that the microinjection of interleukin (IL)-2 into the third ventricle of conscious rats evokes the release of adrenocorticotropin hormone (ACTH) and that its incubation with hemipituitaries in vitro was also effective in releasing ACTH. In the present experiments, we evaluated the effect of IL-2 on the release of corticotropin-releasing factor (CRF) from medial basal hypothalami (MBHs) incubated in vitro and studied the effect of other agents, whose release is altered in stress, on CRF release. IL-2 significantly stimulated CRF release at concentrations of 10(-13) and 10(-14) M, whereas increasing the concentration to 10(-12) to 10(-10) M did not produce significant release of CRF. A high concentration of potassium (55 mM) in the medium also significantly stimulated CRF release and this stimulation was not modified by IL-2. Since high-potassium-induced release of CRF is probably due to opening of voltage-dependent calcium channels, it is likely that IL-2 is releasing CRF by this mechanism. Since the release of luteinizing-hormone-releasing hormone (LHRH) is modified by stress, we evaluated the action of LHRH on CRF release and the release induced by IL-2. Although LHRH failed to alter basal CRF release, except for a slight decrease at 10(-7) M, it completely blocked IL-2-induced CRF release at this concentration. To examine a possible role for opioid peptides in CRF release, the opiate receptor blocker, naloxone (NAL), was tested. At concentrations of 5 x 10(-6) and 10(-5) M, it produced a marked increase in CRF release; however, the simultaneous exposure of MBHs to each of these concentrations of NAL plus IL-2 caused a dose-dependent decrease in IL-2-induced CRF release, suggesting that beta-endorphin or other opioid peptides may play a role in IL-2-induced CRF release. As has been previously shown for IL-1 and IL-6, IL-2-induced CRF release was blocked by alpha-melanocyte-stimulating hormone (alpha-MSH), which at high concentrations also reduced basal CRF release. As in the case of IL-1 and IL-2, dexamethasone (DEX), the highly active synthetic glucocorticoid, although not altering basal CRF release, completely blocked the response to IL-2. The inhibitor of cyclooxygenase, indomethacin (IND), also blocked IL-2-induced CRF release just as it has previously been shown to block IL-1- and IL-6-induced CRF release. The results are consistent with the hypothesis that IL-2 acts on its recently discovered receptors to induce an increase in intracellular calcium. In other experiments, we have shown that this activates nitric oxide (NO) synthase leading to production of NO by a NOergic neuron. NO diffuses to the CRF neuron and activates cyclo-oxygenase leading to generation of prostaglandin E2, which activates adenylate cyclase and increases cyclic AMP release, which then causes extrusion of CRF secretory granules. DEX presumably acts on its receptors on the CRF neuron to inhibit the increase in intracellular calcium and thereby blocks activation of phospholipase A2 necessary for activation of the arachidonic acid cascade. alpha-MSH and LHRH may similarly act on their receptors on these cells to, in some manner, block the pathway. On the other hand, beta-endorphin and/or other opioid peptides inhibit the pathway. Further experiments will be necessary to elucidate the exact points in the pathway at which these compounds are effective.
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PMID:Effects of luteinizing-hormone-releasing hormone, alpha-melanocyte-stimulating hormone, naloxone, dexamethasone and indomethacin on interleukin-2-induced corticotropin-releasing factor release. 864 67

To elucidate the role of specific proinflammatory cytokines in regulating airway responsiveness, we examined the effects and mechanisms of action of IL-1beta, TNF-alpha, and IL-2 on the beta-adrenoceptor- and postreceptor-coupled transmembrane signaling mechanisms regulating relaxation in isolated rabbit tracheal smooth muscle (TSM) segments. During half-maximal isometric contraction of the tissues with acetylcholine, relaxation responses to isoproterenol, PGE2, and forskolin were separately compared in control (untreated) TSM and tissues incubated for 18 h with IL-1beta (10 ng/ml), TNF-(alpha (100 ng/ml), or IL-2 (200 ng/ml). Relative to controls, IL-1beta- and TNF-alpha-treated TSM, but not IL-2-treated tissues, depicted significant attenuation of their maximal relaxation and sensitivity (i.e., -log dose producing 50% maximal relaxation) to isoproterenol (P < 0.001) and PGE2 (P < 0.05); whereas the relaxation responses to direct stimulation of adenylate cyclase with forskolin were similar in the control and cytokine-treated tissues. Further, the attenuated relaxation to isoproterenol and PGE2 was ablated in the IL-1beta-treated TSM that were pretreated with either the muscarinic M2-receptor antagonist, methoctramine (10(-6) M), or pertussis toxin (100 ng/ml). Moreover, Western immunoblot analysis demonstrated that: (a) Gi protein expression was significantly enhanced in membrane fractions isolated from IL-1beta-treated TSM; and (b) the latter was largely attributed to induced enhanced expression of the Gi alpha2 and Gi alpha3 subunits. Collectively, these observations provide new evidence demonstrating that IL-lbeta and TNF-alpha induce impaired receptor-coupled airway relaxation in naive TSM, and that the latter effect is associated with increased muscarinic M2-receptor/Gi protein-coupled expression and function.
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PMID:Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle. 864 53

Vasoactive intestinal peptide (VIP) belongs to an ever growing family of neuropeptides with immunomodulatory functions. VIP-containing nerve fibers are present in both primary and secondary lymphoid organs, frequently in close proximity to immune cells. In addition, several types of immune cells, including T lymphocytes may function as local VIP sources in the lymphoid microenvironment. VIP released from neuronal and/or non neuronal sources exerts immunomodulatory effects through direct binding to VIP receptors (VIP-Rs), which are expressed on most immune cells. The existence of lymphocytic VIP-Rs has been demonstrated initially through binding studies, and more recently, through molecular biology technology. Both VIP-R1 and VIP-R2, which express high affinity for VIP and related neuropeptides such as the pituitary adenylate cyclase activating peptide (PACAP), are present on lymphocyte subsets, and recent reports suggest that whereas VIP-R1 is expressed constitutively, VIP-R2 expression is induced upon lymphocyte activation. Although VIP affects a variety of immune functions, its primary immunomodulatory function seems to be anti-inflammatory in nature. Whereas a rapid inflammatory response is essential for the ultimate elimination of foreign antigens, its intensity and duration have to be strictly controlled to avoid extensive tissue damage. In this respect, neuropeptides with anti-inflammatory functions such as VIP or the structurally related PACAP, timely released within the lymphoid organs, could play an important physiological role in the down-regulation of the immune response. Cytokines, soluble products of immune cells, play major roles in lymphocyte development, activation, and differentiation. As most cytokines are functionally pleiotropic, redundant, and interdependent, local interactions within the cytokine-neuroendocrine network have significant impact on cytokine production and function. Therefore, the immunomodulatory activities of VIP could be mediated, at least partially, through effects on the production of cytokines. The purpose of this article is to review the existing information regarding the VIP modulation of cytokine expression in immune cells. Both VIP and PACAP downregulate the expression of IL-2 mRNA and protein in T cells activated through the T cell receptor, through reducing both the stability and the de novo transcriptional rate of the IL-2 message. Reduction in the amount of IL-2 generated by the activated CD4+ T cells impacts on both T cell proliferation and on further sequential cytokine production. This is indeed the case with IL-4, which is affected by VIP indirectly, through inhibition of IL-2. In contrast, the inhibitory effect of VIP and PACAP on IL-10 production proceeds through a direct transcriptional event. In contrast to IL-2 which functions solely as a proinflammatory cytokine, IL-4 and IL-10 act as pro- or anti-inflammatory cytokines, depending on their involvement in specific immune responses. Therefore, depending on interactions with the local cytokine network, VIP and related neuropeptides may contribute significantly to controlling the amplitude and timing of the inflammatory response to foreign antigens. Although the role of VIP and related peptides on T cell development has not been investigated yet, the presence of VIP and VIP-Rs in the thymus, and their effect on thymic cytokine production, suggests that VIP and/or PACAP released locally within the thymic environment could also affect T cell development, and therefore participate in the generation and maturation of immune cells.
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PMID:Regulatory effects of vasoactive intestinal peptide on cytokine production in central and peripheral lymphoid organs. 879 Jul 82

The release of histamine from mast cells and basophils during allergic reactions can regulate functions of T cells and may influence the nature of the immune response to a given antigen. The effects of histamine on T lymphocytes are associated with its binding to H2-receptors linked with adenylate cyclase, elevation of cAMP levels and activation of cAMP-dependent protein kinase (PKA). In this report we explore the role of PKA in histamine-mediated effects on IL-2 mRNA expression and IL-2 protein secretion. Fresh isolated mouse splenocytes (C57Bl/6) were pretreated with histamine (10(-4) M) for 1 h in the presence or absence of Rp-cAMPS (50 microM), an inhibitor of PKA regulatory subunit. The cells were then washed thoroughly and activated with plate-bound anti-CD3 (5 microg/ml), or PHA (1:100) or PMA + ionomycin (10 ng/ml, 1 microg/ml) for 6 h. Pretreatment with histamine inhibited IL-2 mRNA expression and secretion in cells activated with anti-CD3 or PMA, but not in cells activated with PMA + ionomycin. Rp-cAMPS prevented histamine-mediated suppression and did not itself affect IL-2 production. These results provide evidence that histamine affected IL-2 production when the cells were activated via the T cell receptor (TCR)/CD3 complex, but did not interfere with signal transduction pathways downstream of PKC leading to production of IL-2. These effects of histamine on IL-2 secretion and mRNA expression were mediated via PKA.
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PMID:Involvement of protein kinase A in histamine-mediated inhibition of IL-2 mRNA expression in mouse splenocytes. 1010 90

The immune surveillance hypothesis suggests impaired immune responses to participate in development of cancer. This may partly be due to increased amounts of PGE2 and histamine, which inhibit cellular immunity. These effects are mediated by cAMP, which is increased and thereby may down-regulate IL-2 and its receptor proteins in T helper cells. The proliferative responses and IL-2 synthesis of PBMC have earlier been shown to be reduced in patients with colon cancer. Recently immune modulating agents have been demonstrated to increase the proliferative response of PBMC in vitro, probably by inhibition of adenylate cyclase activity and induction of IL-2 mRNA expression. We have therefore studied the proliferative responses of PBMC from colon cancer patients to PWM and tested the effect of immune modulating agents, such as Serotonin, Sumatriptan, and Buspirone on these PBMC. We found no difference in levels of intracellular cAMP, IL-2 mRNA expression, IL-2R mRNA expression, or proliferative responses of PBMC from colon cancer patients compared to healthy blood donors. There was no effect of the immune modulating agents on PBMC from colon cancer patients.
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PMID:Various functions of PBMC from colon cancer patients are not decreased compared to healthy blood donors. 1085 50

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

The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP, IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces, which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB.
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PMID:Effect of cardiopulmonary bypass on beta adrenergic receptor-adenylate cyclase system on surfaces of peripheral lymphocytes. 1284 65

It is reported that antimycotic agents are effective for the treatment of patients with atopic dermatitis (AD). We studied in vitro effects of antimycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from AD patients and normal donors. The amounts of interleukin-4 (IL-4) and IL-5 secreted by anti-CD3/CD28-stimulated T cells were higher in AD patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole and non-azole terbinafine hydrochloride and tolnaftate reduced IL-4 and IL-5 secretion without altering that of IFN-gamma and IL-2 in anti-CD3/CD28-stimulated T cells from both AD patients and normal donors. The azole derivatives were more inhibitory than non-azole antimycotics. These antimycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for IL-4 and IL-5. The cAMP analogue dibutyryl cAMP reversed the inhibitory effects of the antimycotics on IL-4 and IL-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular cAMP in T cells, and the increase was greater in AD patients than in normal donors. The increase of cAMP by anti-CD3/CD28 correlated with IL-4 and IL-5 secretion by anti-CD3/CD28. The transient cAMP increase was suppressed by antimycotics, and azole derivatives were more suppressive than non-azoles. Azole derivatives inhibited the activity of cAMP-synthesizing adenylate cyclase while terbinafine hydrochloride and tolnaftate enhanced the activity of cAMP-hydrolyzing cyclic nucleotide phosphodiesterase in AD and normal T cells. These results suggest that the antimycotics may suppress IL-4 and IL-5 production by reducing cAMP signal, and strengthen the concept of their potential use for the suppression of T helper-2-mediated allergic reactions.
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PMID:[Antimycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis]. 1528 27


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