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)

Human recombinant interleukin-2 and rat recombinant IL-2 microinjected into the locus coeruleus of rats, induced typical dose-dependent behavioural sedation and/or sleep and electrocortical synchronization. During sleep induced by this lymphokine a dose-dependent increase in total voltage power (0.25-16 Hz) as well as in the 0.25-3, 3-6 and 6-9 Hz frequency bands was observed. The behavioural and electrocortical effects of interleukin-2 were blocked in animals pretreated with anti-IL-2 monoclonal antibodies and with naloxone, whereas they were still evident in rats pretreated with yohimbine. In addition, the behavioural and electrocortical slow-wave sleep effects observed after the administration of interleukin-2 into the locus coeruleus were reduced significantly or antagonized completely by a previous pretreatment with pertussis toxin, forskolin, dibutyryl-cyclic-AMP and 8-bromo-cyclic-AMP. These results are consistent with the hypothesis that the behavioural and electrocortical changes of this lymphokine are mediated at locus coeruleus level via a guanine regulatory Gi protein coupling IL-2 specific receptors to the adenylate cyclase system.
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PMID:Effects of pertussis toxin, dibutyryl-cyclic-AMP, bromo-cyclic-AMP and forskolin on the behavioural and electrocortical power spectrum changes induced by microinfusion of interleukin-2 into the locus coeruleus. 166 94

Morphine, a potent analgesic drug as well as the active metabolite derived from heroin, has been reported to affect a variety of immune functions. In vivo administration of high doses of morphine to animals has been shown to inhibit natural killer (NK) cell activity in the rat (Shavit et al., 1984) and splenic T cell mitogenic response in the mouse (Bryant et al., 1988). We report here on the effect of morphine sulfate (MS) (0.2-1.6 mM) on Concanavalin-A (Con-A) stimulated lymphokine production by mouse splenocytes in vitro. Twenty-four hour incubation of mouse splenocytes with MS, removal of the drug and activation with Con-A resulted in a significant (linear regression, P less than 0.001) dose-related inhibition of lymphokine production (IC50 = 0.8 mM) as measured by bioassay for interleukin-2 (IL-2)/interleukin-4 (IL-4). The inhibitory effect of MS on lymphokine production was not blocked by opiate antagonists nor was the inhibitory effect mimicked by equivalent concentrations of mu, delta or epsilon receptor-specific opiate agonists. Exposure to the concentrations of MS used did not reduce viability of mouse splenocytes as determined by Trypan Blue exclusion. Morphine did not inhibit protein synthesis or adenylate cyclase activity in a T cell clone under identical conditions, indicating that MS, in this concentration range, does not simply interfere with all cell functions in a nonspecific manner. These results suggest that (1) morphine directly inhibits splenocyte function, (2) the inhibitory effect is not mediated through classical opiate receptors, and (3) the inhibitory effect is not due to toxicity.
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PMID:Effect of high doses of morphine on Con-A induced lymphokine production in vitro. 166 96

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

Previous studies have shown that maturational changes can be induced in a human monocyte line, U937, by treatment with cellfree medium from lectin-stimulated cloned human T lymphocytes or the vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3). Many of the maturational effects are accompanied by modification, new synthesis, or reorganization of cell surface membrane constituents, including proteins that function as receptors for ligands that modulate monocyte function. In the present studies, we examined the effects of monocyte differentiation on responsiveness to prostaglandin E2 (PGE)2. We found that the maturational effects of the lymphokine or 1,25[OH]2D3 were accompanied by a marked reduction in the PGE2-induced increase in cellular content of adenosine 3':5'-cyclic monophosphate (cAMP) and a shift in the dose-response curve consistent with a decrease in PGE2 receptor number or binding affinity. Incubation of cells with IFN-alpha or IFN-gamma produced by recombinant DNA technology did not influence PGE2 responsiveness, suggesting that the effects of the lymphokine were not mediated by these products. The absence of an effect on sodium fluoride- or forskolin-induced adenylate cyclase response in membranes prepared from treated cells suggests that the treatment conditions affect PGE2 receptor function rather than the adenylate cyclase enzyme complex. Changes in cell surface receptors for hormones such as PGE2 provide a potential mechanism for modulating the biologic activity of monocyte-macrophages during the process of cellular differentiation.
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PMID:The adenosine 3':5'-cyclic monophosphate response to prostaglandin E2 is altered in U937 cells in association with maturational events induced by activated T lymphocytes and 1,25-dihydroxyvitamin D3. 242 Aug 90

Interleukin 2 (IL-2) stimulated the differentiation of human peripheral blood leukocytes into lymphokine-activated killer cells, as well as DNA synthesis of human T lymphocytes. Both effects of IL-2 could be inhibited by prostaglandin E2, a potent stimulator of adenylate cyclase; however, the inhibitory effect of prostaglandin E2 could be overcome by increased concentrations of IL-2. The opposite effects of IL-2 and prostaglandin E2 were paralleled by their respective abilities to inhibit and stimulate cAMP production in intact cells. Other agents, which inhibit adenylate cyclase directly (somatostatin, beta-endorphin, UK 14.3041) or indirectly by activation of protein kinase C (phenylephrine), could stimulate both differentiation and proliferation. None of these agents alone or in combination were as effective as maximal concentrations of IL-2. However, all agents potentiated differentiation and proliferation induced by submaximal and maximal concentrations of IL-2. Additionally, combinations of agents which stimulated protein kinase C with those that inhibited adenylate cyclase were additive in the potentiation of IL-2-induced differentiation. Neither inhibition nor potentiation of IL-2-induced lymphokine-activated killer cell differentiation was accompanied by changes in Tac expression or gamma-interferon production. The data indicate that the stimulation of lymphokine-activated killer cell differentiation and lymphocyte proliferation in human cells share a common initial biochemical signal. Although the inhibition of adenylate cyclase is not sufficient to maximally stimulate either process and cannot bypass the requirement for IL-2, modulation of this enzyme complex, positively or negatively, can regulate the ultimate physiologic response to IL-2.
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PMID:Potentiation of lymphokine-activated killer cell differentiation and lymphocyte proliferation by stimulation of protein kinase C or inhibition of adenylate cyclase. 244 68

Polyclonal differentiation of unprimed B cells into IgM-producing cells induced by lipopolysaccharide (LPS) or T cell-derived lymphokine B151-TRF2 has been shown to contain a process of I-A-restricted B-B cell interaction, so that the B cell responses are inhibited by monoclonal antibodies (mAb) specific for I-A molecules. On the other hand, the B cell responses are also inhibited by anti-I-E mAb, although I-E molecules are not involved in such B-B cell interaction. In this study, we examined the mechanism underlying the anti-I-E-mediated inhibition of the B cell responses. The B cell responses induced by LPS or B151-TRF2 were inhibited by either anti-I-A or anti-I-E mAb added on day 0 over a 5-day culture period, whereas when added on day 3 the responses were inhibited only by anti-I-E mAb and not by anti-I-A mAb. To gain insight into the mechanism underlying the anti-I-E-mediated inhibition, we prepared monovalent Fab and divalent F(ab')2 fragments of anti-I-A and anti-I-E mAb and examined their effects on the B cell responses. We found that the B cell responses were inhibited by the F(ab')2 but not Fab fragment of anti-I-E mAb, whereas the Fab fragment of anti-I-A mAb still gave effective inhibition. The F(ab')2 but not Fab fragment of anti-I-E mAb induced increases in cyclic AMP (cAMP) levels in B cells, whereas the undigested anti-I-A mAb did not induce such increases. Furthermore, adenylate cyclase inhibitors, which inhibit cellular cAMP accumulation, circumvented the B cell responses inhibited by anti-I-E but not anti-I-A mAb. Thus, these results indicate that the anti-I-E-mediated inhibition of the B cell responses requires increases in intracellular cAMP levels induced by cross-linking of I-E molecules. In contrast, anti-I-A mAb inhibits the B cell responses without cross-linking of I-A molecules and cAMP accumulation. These results reinforce a unique function of I-A molecules as restriction elements in the Ia-restricted B-B cell interaction.
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PMID:Disparate functions of I-A and I-E molecules on B cells as evidenced by the inhibition with anti-I-A and anti-I-E antibodies of polyclonal B cell activation. 255 20

Vasoactive intestinal peptide (VIP) induces phosphorylation of a basic 38,000 mol. wt protein in a human lymphoblastic cell line (Molt 4b) and a human colon carcinoma cell line (HT29). In both cell types, VIP interacts with specific high affinity receptors to activate adenylate cyclase and cAMP-dependent protein kinase. The two cell types appear to express homologous receptors with similar affinity and specificity for VIP, but the colonic epithelial cells express a greater number of receptors. HT29 colonic cells also exhibit a greater stimulation of adenylate cyclase and a higher phosphorylation index for the 38,000 mol. wt protein in response to VIP. This 38,000 mol. wt protein, which is phosphorylated in the presence of VIP, appears to be identical in both cell lines; it is phosphorylated in both lymphoblasts and colonic epithelial cells in the presence of forskolin, but not in the presence of phorbol 12-myristate 13-acetate. Phosphorylation of this 38,000 mol. wt protein may be an important step in VIP regulation of water and electrolyte secretion from colonic epithelial cells, and in VIP regulation of immunoglobulin and lymphokine secretion from lymphocytes.
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PMID:Comparison of vasoactive intestinal peptide-mediated protein phosphorylation in human lymphoblasts and colonic epithelial cells. 277 Jul 50

The expression of the interleukin-2 receptor (IL-2-R) is regulated by transcriptional and post-transcriptional mechanisms. IL-2-R gene expression is induced by pharmacological agents including calcium ions, phorbol esters such as phorbol myristate acetate (PMA) and forskolin (FK), a direct activator of adenylate cyclase. HTLV-I(+) leukemic T cells and T cell lines from patients with adult T cell leukemia (ATL) continuously expressed IL-2-R without production of IL-2. However, there was no abnormality of the structural gene for IL-2-R in these cell lines as well as in fresh leukemic cells of ATL. We have detected that many HTLV-I(+) T4(+) T cell lines constitutively produce a non-IL-2 lymphokine named ATL-derived factor (ADF), which induced the expression of the high-affinity IL-2-R on a variety of cells including HTLV-I(+) T cells, myeloid leukemia cells and YT cells. IL-2-R-inducing agents such as ADF and FK were shown to induce elevation of the mRNA levels for IL-2-R through transcriptional enhancement of the IL-2-R gene. The possible involvement of IL-2-R-inducing cytokines in the physiological lymphocyte activation and the leukemogenesis in ATL and other T cell leukemias is discussed.
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PMID:Interleukin-2 receptor-inducing factor(s) in adult T cell leukemia. 289 6

Precultured mouse peritoneal macrophages were incubated with a microbial growth inhibitory lymphokine prepared from cell-free ascites of rat Zajdela hepatoma. Cyclic nucleotide metabolism was followed in parallel to experiments demonstrating inhibition of intracellular growth of Corynebacterium murium kutscheri. Maximum increase of cAMP, adenylate cyclase and cAMP-phosphodiesterase activities was found after 60 to 90 min, while inhibition of microbial growth was evident only after 2-3 h. Both effects showed concordant dose dependence. It is concluded that cAMP induces cellular metabolic changes which lead to inhibition of bacterial growth by macrophages.
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PMID:Effect of a microbial growth inhibitory factor on the cyclic nucleotide metabolism of peritoneal macrophages. 626 1

T and B lymphocytes of human or murine origin were found to secrete a factor which increases the DNA and RNA synthesis of cultured glia cells. This factor, termed glia cell stimulating factor (GSF), is released upon stimulation of such immune cells by mitogen or antigen qualifying it as a lymphokine. In this communication we report on the role of cyclic AMP (cAMP) in regulating the effect of GSF on glia cells. Prostaglandin E1 (PGE1), isoproterenol and theophylline were effective in suppressing the GSF-induced increase of the glia cell proliferation. No inhibition of DNA synthesis and no decrease in cell number was observed when testing these substances on glia cells not being activated by GSF. The drugs were found to induce an increase in cAMP concentrations of glia cells. A partial desensitization of the glia cells to these drug induced elevations of cAMP was detected after pretreatment of the glia cell cultures with GSF. It is suggested that stimulated lymphocytes not only release GSF but also low molecular weight proteins such as PGE1 which regulate the effects of GSF on glia cells by activating their adenylate cyclase.
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PMID:Involvement of cyclic AMP in the regulations of lymphokine induced glia cell stimulation. 627 47


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