Camp inhibits the okt3- induced increase in cytoplasmic free calcium in the jurkat t cell line: the degree of inhibition correlates inversely with the amount of cd3 binding ligand used* (original) (raw)
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Journal of Leukocyte Biology, 2006
We have previously shown that cholera toxin (CT) and other cAMP-elevating agents induce up-regulation of the inhibitory molecule CTLA-4 on human resting T lymphocytes. In this study, we evaluated the function of these cells. We found that purified human CD4+ T lymphocytes pretreated with CT were able to inhibit proliferation of autologous PBMC in a dose-dependent manner. It is interesting that this phenomenon was not mediated by inhibitory cytokines such as IL-10, IL-4, or TGF-β but was in part caused by the release of extracellular cAMP by the CD4+ T lymphocytes. Purified CD4+ T cells pretreated with forskolin, a transient cAMP inducer, or with dibutyryl cAMP, an analog of cAMP, did not exert suppressive functions, suggesting that a sustained production of cAMP, such as that induced by CT, was required to identify a novel regulatory function mediated by CD4+ T cells. Our results show that CD4+ T lymphocytes can exert regulatory functions through the release of extracellular cAMP an...
The Journal of Immunology
Dibutyryl cAMP and IL 1 were found to stimulate antigen-specific and polyclonal antibody production when added together to cultures of highly purified B cells. We propose that IL 1 and an elevation in cytoplasmic cAMP represent minimal signal requirements for B cell activation. In contrast to its effect on B cells, dibutyryl cAMP inhibited helper T cell activity. Cyclic AMP suppressed the production of IL 2 and T cell replacing factor (TRF) by T cells and thus abrogated the ability of helper T cells to enhance SRBC-specific antibody production by B cells. Cyclic AMP did not inhibit the generation by T cells of B cell growth factor (BCGF). BCGF, not normally detected in Con A supernatant, was found in the culture supernatant of spleen cells that were stimulated with Con A in the presence of cAMP. Our findings indicate that cAMP blocks the production of an inhibitor of BCGF activity. cAMP had no effect on the production by macrophages of IL 1.
Frontiers in Immunology, 2016
We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4 + T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4 + CD25 + T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4 + CD25 − and further enhance its expression in CD4 + CD25 + T cells. We observed an increase of two isoforms of mRNA coding for the membrane and the soluble CTLA-4 molecules, suggesting that the regulation of CTLA-4 expression by cAMP is at the transcriptional level. In addition, we found that the increase of cAMP in CD4 + CD25 + T cells converts the CD4 + CD25 + Foxp3 − T cells in CD4 + CD25 + Foxp3 + T cells, whereas the increase of cAMP in CD4 + CD25 − T cells did not upregulate Foxp3 in the absence of activation stimuli. To investigate the function of these cells, we performed an in vitro suppression assay by culturing CD4 + CD25 + T cells untreated or pre-treated with CT with anti-CD3 mAbs-stimulated autologous peripheral blood mononuclear cell. We found that CT enhances the inhibitory function of CD4 + CD25 + T cells, CD4 + , and CD8 + T cell proliferation and IFNγ production are strongly inhibited by CD4 + CD25 + T cells pre-treated with cAMP-elevating agents. Furthermore, we found that CD4 + CD25 + T lymphocytes pre-treated with cAMP-elevating agents induce the upregulation of CD80 and CD86 co-stimulatory molecules on immature dendritic cells (DCs) in the absence of antigenic stimulation, however without leading to full DC maturation. These data show that the increase of intracellular cAMP modulates the phenotype and function of human CD4 + CD25 + T cells.
Role of cAMP in regulating cytotoxic T lymphocyte adhesion and motility
European Journal of Immunology, 1993
We investigated the functional role of the CAMP pathway in human cytotoxic T lymphocyte (CTL)-target interaction. Pharmacological increase of intracellular CAMP concentration C CAMP]^) inhibits killing, especially at low effectorto-target ratios, suggesting an inhibitory effect on CTL recycling. We show that this inhibitory effect is primarily at the level of conjugate formation. Pharmacological increase in [cAMP]i, as well as treatment with cytochalasin D, results in a "rounding up" of the CTL and inhibition of the dramatic changes in shape that occur when a CTL forms a conjugate, even with an irrelevant target. In addition, pharmacological increase in [cAMP]i affects the cytoskeleton of the CTL since it induces a decrease of filamentous actin, as detected by flow cytometry on phalloidin-stained CTL, and a stabilization of microtubules, as detected by increased resistance to the disrupting action of nocodazole. In mature CTL (but not in their immature precursors), Tcell receptor triggering by specific targets results in a measurable increase in CAMP levels and strongly synergizes with adenylyl cyclase activators such as prostaglandin E2, cholera toxin and forskolin. We suggest that Tcell receptor triggering may induce accumulation of cAMP that interferes with cytoskeleton function and, thus, terminates CTL secretion and adhesion. These effects of cAMP are rapidly reversible and may regulate CTL recycling.
Immunopharmacology, 1999
The role of the cAMP pathway as an immunomodulatory system has been an area of intensive research. Pharmacological elevation of the cAMP pathway inhibits T lymphocyte proliferation and production of Th1-type cytokines. The effects of Ž. cAMP are thought to be mediated via activation of the intracellular receptor, protein kinase A PKA. We investigated the inhibitory effects of cAMP elevation on human lymphocyte proliferation and function by utilising a range of selective inhibitors of PKA. Elevation of cAMP activity by dbcAMP, Sp-cAMPS and forskolin induced significant decreases of Con A stimulated PBMC proliferation. Co-incubation with the selective PKA inhibitors HA1004, KT5720 and Rp-cAMPS showed these antiproliferative effects to persist, despite measurable PKA activity being inhibited to that of untreated cells or less. IL-2 production was also inhibited by dbcAMP in the presence of HA1004 and Rp-cAMPS. It has been demonstrated that the inhibitory effects of pharmacological elevations in cAMP on human T cell proliferation and IL-2 production do not require PKA activity. These observations indicate that control of lymphocyte proliferation and functional status by cAMP proceeds through PKA-independent events. Identification of the underlying mechanisms behind these effects would increase our understanding of the cAMP cascade and may provide a potentially novel target for immunomodulation.
Cellular Immunology, 1990
We have studied the effects of prostaglandin E2 (PGE2) and cholera toxin, two modulators of adenylyl cyclase, and 8-bromo CAMP (8-BrcAMP) on various parameters of lymphocyte activation using the human T cell line Jurkat. Our results show that PGE2 and cholera toxin inhibit, in a dose-related manner, the phytohemagglutinin (PHA)-dependent production of interleukin 2 by these cells. The data are consistent with the interpretation that the inhibition is due to an intracellular increase in CAMP, since the metabolically stable 8BrcAMP analog produced the same inhibitory effect. However, PGE2 or 8-BrcAMP did not interfere with the PHAinduced elevation in the cytosolic concentration of Ca*+, suggesting that changes in the intracellular concentration ofcAMP does not affect the internal release or the influx of Ca*+. In contrast, cholera toxin prevented the Ca*+ response of Jurkat cells to PHA. We studied the effects of PGEZ, cholera toxin, and 8-BrcAMP on the amplitude of the K+ outward current using the patch clamp technique in the whole cell configuration. Results showed that PGE2,8-BrcAMP, and cholera toxin inhibited K+ channel activity. For instance, the amplitude of the outward K+ current was reduced to 43 f 19%, 50 + 26%, and 46 f 16% ofcontrol values in the case of cells perfused in the presence of PGE2, 8-BrcAMP, and cholera toxin, respectively. Blocking K+ channels with tetraethylammonium ions did not prevent the characteristic Jurkat Ca*+ response to PHA. Our observations that CAMP inhibits K+ channel activity in a T cell line provide an additional explanation for its reported inhibition of lymphocyte activation. Increasing the intracellular concentration ofcAMP may result in reduction of K+ movements and in negative modulation of signal transduction via G-proteins as previously suggested. These two effects could act in synergy to impair signal transduction. 0 1990 Academic press, IIIC.
Journal of leukocyte biology, 1994
Drugs that elevate cAMP levels in human basophils are known to inhibit immunoglobulin E (IgE)-mediated histamine release. We have examined whether cAMP-active agents inhibit the cytosolic Ca2+, [Ca2+]i, response that normally accompanies activation of basophils. As previously described, this [Ca2+]i response is biphasic, one phase dependent on internal sources of calcium and a second later phase dependent on extracellular calcium, as observed in many cell types. Forskolin and rolipram or their combination had no effect on the initial elevation of cytosolic calcium that follows stimulation with anti-IgE antibody. In contrast, the second phase of the IgE-mediated calcium response was inhibited by these agents. For IgE-mediated responses, the relative efficacy of various cAMP active agents (rolipram approximately forskolin < dibutyryl cAMP < forskolin + rolipram) for the inhibition of histamine release and the second-phase calcium response was similar and roughly paralleled the m...
Biochemical Society Transactions, 2000
The earliest second messenger discovered was the CAMP. cAMP weakly penetrates into the cell. O n the other hand, dibutyryl cAMP is membrane-penetratible derivative of the CAMP, which shows high activity and at present time is largerly used in experiments. The comparative study of the effects of cAMP and dibutyryl cAMP on the structure of monoolein-water cubic liquid-crystalline phase have been performed by X-ray diffraction, Raman, and FTIR spectroscopies. Based on the X-ray diffraction data it was established that cAMP does not change the structure of Pn3m lattice, contrary to dibutyryl cAMP which induces transformation from Pn3m to Ia3d lattice. The H-bonding interaction between the anionic phosphate group of cAMP and the glycerol backbone of the lipids has been evidenced by the increased frequency of the symmetric stretching vibration of PO2 group by 4-6 cm-l and broadening by 7 cm-l of the stretching vibration of glycerol C-OH group. It was found that dibutyryl cAMP interacts with the cubic phase through the pyrimidine ring and contrary to cAMP shows tendency to increase the number of gauche defects and to lower the mobility of the acyl chains.= 970 Proteasomes regulate the duration of erythropoietin receptor activation by controlling down-regulation of cell surface receptors