The antagonistic action of cyclic GMP and cyclic AMP on proliferation of B and T lymphocytes.

The effect of c-AMP, c-GMP and both substances together on (3H)-thymidine incorporation into nuclear DNA was investigated using spleen cells of normal and athymic nude mice. c-GMP induces DNA synthesis in both normal and nude spleen cell populations. c-AMP inhibited the stimulatory activity of c-GMP as well as the phytohaemagglutinin (PHA) and lipopolysaccharide (LPS) response of spleen cells. The inhibitory activity of c-AMP on the PHA and LPS responses can be reversed by c-GMP. The possible role of cyclic nucleotides in the regulation of cell proliferation and of the immune response is discussed.     

Changes in intracellular cyclic AMP levels of human peripheral blood lymphocytes in bronchial asthma.

Peripheral blood lymphocytes of asthmatic patients in the acute stage manifest low basal levels of cyclic AMP. These levels were higher in the lymphocytes of patients in remission than in controls. Trypsin treatment of the lymphocytes increased cyclic AMP content to almost the same additional activation site of the receptor in theophylline- and catecholamines-treated patients.     

IgE-induced changes in human basophil cyclic AMP levels.

We studied a unique patient with 77% basophils, not different from normal by a number of criteria, in order to measure the changes in cyclic AMP level associated with IgE-mediated histamine release. In accordance with previous hypothesis and circumstantial evidence, anti-IgE challenge led to a significant fall in the cyclic AMP level which preceded histamine release.     

Effects of platelet activating factor on cyclic AMP accumulation in human lymphocytes.

The in vitro effects of platelet activating factor (PAF) on intracellular adenosine 3',5'-cyclic adenosine monophosphate (cAMP) accumulation were assessed in human lymphocytes in ten healthy volunteers and in eight asthmatic patients. Platelet activating factor to increased intracellular cAMP in both groups. In addition, PAF also enhanced the effects of isoproterenol and theophylline on intracellular cAMP production in these two groups.     

The stimulation of human B and T lymphocytes by various lectins

The response of human peripheral blood lymphocytes to different lectins was tested in vitro by monitoring DNA synthesis, blast transformation, and mitotic activity. One group of lectins - RCA, VGA, HPA, PNA, and UEA - showed no stimulating effects at all. WGA and VVA induced DNA synthesis and blast transformation but failed in stimulating mitosis. The mitogens PHA, ConA, LCA, and PWM showed peaks of mitotic activity at 50-60 hours for PHA, 70 hours for ConA, 80 hours for LCA, and between days 4 and 5 for PWM. The stimulation of different subpopulations of lymphocytes was investigated by immunological methods for the detection of B- and T-cell-specific surface structures during the whole incubation period. PHA proved to be a predominantly T cell stimulating agent, whereas ConA seemed to activate a higher proportion of B cells than yet known. PWM and the so-called T cell mitogen LCA turned up to stimulate a large number of B cells, but lead also to a T cell activation. The analysis of SCE events in stimulation experiments with these two lectins showed the early proliferation of a cell population with low SCE frequencies and the late propagation of a cell population with higher SCE rates. It could be assumed that the first population is represented by B- and the second by T-cells.     

Absence of the effect of ephedrine on levels of cyclic adenosine monophosphate in human lymphocytes.

Concentrations of 10(-6) to 10(-3) M ephedrine did not increase cyclic adenosine monophosphate (cAMP) levels of normal human lymphocytes even in the presence of theophylline or cortisol, which enhance the response to isoproterenol or prostaglandin E1. Preincubation for 2 hr with ephedrine did not reduce the subsequent effect of isoproterenol, although preincubation with isoproterenol itself did. Therefore, ephedrine is not a direct beta-adrenergic agonist on human peripheral blood lymphocytes.     

Activation of human B lymphocytes VII. the regulatory effect of cyclic adenosine monophosphate on human B cell activation.

Cyclic adenosine monophosphate (cAMP) has been demonstrated to play an integral role in the regulation of B cell activation. By employing a plaque-forming cell (PFC) assay for polyclonal activation of human B lymphocytes, it was demonstrated that dibutyryl cyclic adenosine monophosphate (DB-cAMP) markedly increased the PFC response of pokeweed mitogen (PWM)--stimulated lymphocytes. Inducers of intracellular cAMP effected a comparable enhancement. Co-cultures of fresh lymphocytes with autologous T cells which had been pre-incubated with DB-cAMP produced an enhancement of B cell activation by a selective effect on the T cells. The mechanism of action of this enhancement of the B cell response is most likely a relative increase in helper T cell function resulting from a selective inhibition of suppressor T cells.     

Cyclic AMP potentiation of interferon antiviral activity and effect of interferon on cellular cyclic AMP levels.

Treatment of L cells with 3 to 10 mM 3':5'-cyclic adenosine monophosphate (cAMP) in the presence of interferon was found to potentiate the development of antiviral activity. The dose response of interferon activity at various time periods in the presence and absence of cAMP indicated that potentiation of interferon activity by cAMP occurred at an early stage in the development of antiviral activity. Among the analogues of cAMP tested for interferon-potentiating activity, only the acylated derivatives were found to be active. Combined L-epinephrine and theophylline treatment of cells elevated cellular cAMP levels and also potentiated interferon-mediated antiviral activity. Interferon was also found to elevate cAMP levels in L cells. This activity was limited to biologically active interferon and antagonized the depression of cAMP associated with vesicular stomatitis virus (VSV) infection of L cells. These observations suggest that some aspects of interferon's biological activity is associated with an alteration in cellular levels of cAMP.     

Melatonin potentiates cyclic AMP production stimulated by vasoactive intestinal peptide in human lymphocytes.

The present paper demonstrates the effect of melatonin on cyclic AMP production in human lymphocytes from peripheral blood. Melatonin by itself did not influence cyclic AMP accumulation in these cells at any dose studied; however, the drug potentiated the effect of vasoactive intestinal peptide (VIP) on the cyclic nucleotide production. In the presence of physiological concentrations of VIP (either 1, 10 or 100 pM), melatonin potentiated cyclic AMP production. However, at high doses of VIP (either 1, 10 or 100 nM), melatonin exhibited no such effect. The results suggest that human lymphocytes are a target for melatonin and that it may participate, jointly with VIP, in the regulation of immune function.     

The differential effect of cyclic AMP on lymphocyte stimulation by T- or B-cell mitogens.

Dibutyryl-cyclic adenosine 3'5'-monophosphate (cAMP) added to mouse spleen cell cultures under serum free conditions inhibited the stimulation of [3H]thymidine incorporation induced by T-cell mitogens much more than the one induced by B-cell mitogens. The inhibition was most impressive with phytohaemagglutinin, followed by concanavalin A, pokeweed mitogen and the specific antigen Keyhole limpet haemocyanin (KLH). The response to bacterial lipopolysaccharide (LPS) was clearly less susceptible to suppression and the effect on the stimulation induced by trypsin and suramin, both B-cell mitogens, was marginal. Similar results were obtained by addition of isoproterenol or therophyllin to the cultures.     

CD2 is involved in regulating cyclic AMP levels in T cells

The human T lymphocyte-specific CD2 (T11) molecule, that regulates T cell activation, is capable of mediating increases of intracellular cAMP. Monoclonal antibodies directed to different epitopes of the CD2 molecule which either induce or inhibit T cell proliferation are capable of triggering an increase of cAMP comparable to that induced by reagents which activate adenylate cyclase. These results indicate that there is a relationship between the CD2 membrane molecule and the adenylate cyclase system.     

交链孢酚单甲醚对人淋巴细胞内环核苷酸水平的影响

淋巴细胞内环核苷酸水平的变化与免疫功能有关。交链孢酚单甲醚是食管癌高发区河南省林县粮食中分离中的主要污染菌互隔交链孢霉（亦称链格孢菌）的毒素之一，已有实验证实ＡＭＥ具有致突变性和致癌性。本实验从体外探讨了ＡＭＥ对人淋巴细胞内环核苷酸水平的影响。实验结果表明，ＡＭＥ能增高淋巴细胞内ｃＡＭＰ水平，不同浓度的ＡＭＥ在不同作用进点上，使细胞内ｃＡＭＰ含量比相应对照组升高１．５－２．０倍，并且在同一时点，随     

The effect of nerve growth factor on DNA synthesis, cyclic AMP and cyclic GMP accumulation by mouse spleen lymphocytes.

Nerve growth factor (NGF), a trophic neuropeptide, is known to stimulate development, and to be important in the maintenance and survival of sympathetic and sensory neurons. Considering the presence of specific receptors on the surface of spleen cells, the effect of 2.5s nerve growth factor on 3H-thymidine uptake, cAMP and cGMP accumulation in mouse spleen lymphocytes has been studied. It was found that NGF added in vitro at the concentrations between 4 x 10(-7) and 4 x 10(-8) M significantly inhibited the incorporation of 3H-thymidine into lymphocytes DNA and increased cAMP levels in a dose-dependent manner but had no effect on cGMP levels. The maximal stimulation of cAMP synthesis occurred between 5 and 30 min after the NGF addition to the culture medium. When NGF was administered in vivo a significant dose-dependent inhibition of the lymphocytes proliferation was observed. These results indicate that an early increase of cAMP concentration is responsible for the antiproliferative action of NGF on mouse spleen lymphocytes and suggest that NGF could play an important role in the regulation of immune system function.     

Stimulatory and inhibitory effects of cyclic AMP on lymphocytes from atopic children.

The effect of cholera toxin and dibutyryl cAMP on mitogen-activated lymphocytes from atopic and non-atopic individuals was studied. Cholera toxin enhanced stimulation by phytohemagglutinin of cells from small children but not from adults. Dibutyryl cAMP at low concentration (less than 10(-5) M) significantly enhanced the lymphocyte response to mitogens in some, but not all individuals. High concentrations, on the other hand, were consistently inhibitory. In atopic children, the lymphocyte response to T cell mitogen was significantly less stimulated by cholera toxin, and more inhibited by dibutyryl cAMP than the response of cells from non-atopic matched controls. Thus, T cells from atopic individuals appear to have an altered sensitivity to the action of cAMP, possibly resulting in an impaired balance between helper and suppressor T cells. The hypothesis is advanced, that such an altered balance is causally related to hyperproduction of IgE resulting in atopic disease.     

Longitudinal studies showing alterations in the levels and functional response of T and B lymphocytes in human pregnancy.

Altered blood levels of T and B lymphocytes were found in the first half of human pregnancy. A total of twenty-two women were tested, using direct or indirect rosetting assays or the fluorescence-activated cell sorter, to determine the levels of peripheral blood T and B cells. In all cases, an inversion of T- and B-cell levels was observed, i.e. T-cell levels were decreased and B-cell levels (as measured by the presence of surface immunoglobulin or the presence of B-cell surface antigens) were increased. This inversion was exhibited as early as 1 week post-implantation. Lymphocytes from two fo the women were also examined for stimulation with phytohaemagglutinin (PHA) and pokeweed mitogen (PWM) at intervals during gestation, and the amount of [3H]thymidine uptake was compared to that of two non-pregnant women tested at each interval. The values obtained for the pregnant women with PHA were markedly lower, and with pokeweed mitogen slightly lower, than those of non-pregnant controls. However, the PHA and PWM values in the pregnant women returned to levels similar to those of the nonpregnant women shortly after the T- and B-cell levels returned to normal. Thus the decrease in the response of the lymphocytes to mitogens during early pregnancy appears to parallel the numerical deficiency of T cells.     

Effect of streptolysin S on human and mouse T and B lymphocytes.

The effect of streptolysin S on T and B human and mouse lymphocytes was studied. The dose-dependent inhibition of T cell rosette formation was observed, and this was accompanied by a dose-dependent cytotoxicity. The existence of a difference in the degree of susceptibility of T and B cells to the cytotoxic effect of streptolysin S is shown.     

Effect of in vitro x-irradiation on human peripheral blood T and B lymphocytes.

The effect of in vitro irradiation with increasing in logarythmic progress X-ray doses on lymphocyte viability and on T and B lymphocyte populations was studied in normal adults, patients with myasthenia gravis and in patients undergoing long-term steroid therapy. Decrease in numbers of lymphocytes carrying T or B lymphocyte surface markers was higher than viable cell loss. The decrease showed no linear correlation with X-ray doses applied, which might reflect the existence of radioresistant T and B lymphocytes. A higher so called early radiosensitivity of B lymphocytes was demonstrated. In patients with myasthenia gravis early radioresistance of T lymphocytes was detected. In patients undergoing long-term steroid therapy, an increase in numbers of cells lacking markers of any of lymphocyte populations was found in parallel with a decrease in T lymphocyte number which, in these patients, showed a higher radiosensitivity.