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PubMed1992

Selective proliferation of gamma delta T lymphocytes exposed to high doses of ionomycin.

The alpha beta T cell repertoire is primarily shaped in the thymus. However, extrathymic positive selection has been demonstrated for many gamma delta T cell clonotypes. This latter type of selection is the result of a peripheral clonal expansion which could be facilitated by special physiological properties of gamma delta T cells, distinguishing them from most alpha beta T cells. In studying the behavior of T cells under conditions of polyclonal activation, we noticed a differential sensitivity between alpha beta and gamma delta T cells to strong stimulatory signals. When induced with high doses of ionomycin, a large fraction of peripheral gamma delta T cells and a small fraction of alpha beta T cells are able to proliferate exponentially while most alpha beta T cells die. This phenomenon appears to be related to intracellular regulation of high concentrations of cytosolic Ca2+. The ability to proliferate under strong stimulatory conditions is a striking feature of many peripheral gamma delta T cells but not of gamma delta thymocytes. In general, T cells selected in the periphery by clonal expansion might be characterized by resistance to strong stimuli and typically, by their ability to "handle" higher concentrations of free cytoplasmic calcium.

Animals↗

PubMed1991

Purified Fc epsilon R+ bone marrow and splenic non-B, non-T cells are highly enriched in the capacity to produce IL-4 in response to immobilized IgE, IgG2a, or ionomycin.

Non-B, non-T cells from spleen and bone marrow cells produce IL-4 in response to cross-linkage of high affinity receptors for Fc epsilon R or Fc gamma RII, and to treatment with calcium ionophores. Cells bearing high affinity Fc epsilon R constituted 1 to 2% of non-B, non-T cells of spleen and of total bone marrow cells from naive donors. In mice whose immune systems had been polyclonally activated by injection with anti-IgD antibodies or had been infected with Nippostrongylus brasiliensis larvae, the frequency of Fc epsilon R+ cells in splenic non-B, non-T cells was also 1 to 2% but in bone marrow from anti-IgD-injected mice donors the frequency was approximately 5%. Cell sorting experiments revealed that all of the capacity to produce IL-4 in response to immobilized IgE or IgG2a or to ionomycin was found in the Fc epsilon R+ fraction. Among the Fc epsilon R+ spleen cells from naive donors, the frequency of IL-4-producing cells was 1/20 to 1/40 whereas in mice that had been injected with anti-IgD or infected with N. brasiliensis, the frequency of IL-4 producing cells in the Fc epsilon R+ population was approximately 1/5.

Animals↗

PubMed1991

[Release of endothelin from isolated perfused human umbilical vein. I: Effect of ionomycin].

Endothelin-like immunoreactivity (ET-LI) was directly measured in the perfusate from the isolated human umbilical vein perfused with Krebs-Ringer solution. The identity of the immunoreactive peptide was confirmed as ET-1 by high-performance liquid chromatography. The rate of release of ET-LI was 86.7 +/- 25.9 (SE) fmol during the first perfusion period of 30 min, and it remained stable at least for 4 hours. Calcium ionophore ionomycin, added to the perfusion medium (10(-7)-10(-6) M), stimulated the ET-LI release in a dose-dependent fashion; it increased the rate of release by 29.1% and 143.4% over the control at the concentrations of 10(-7) and 10(-6) M, respectively. These results taken together with previous observations of synthesis of ET in cultured vascular endothelium provide direct evidence for local generation and subsequent release of ET from vascular beds of human beings.

Calcium↗

PubMed1990

Ability of the Ca2+ ionophores A23187 and ionomycin to mimic some of the effects of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production, ornithine decarboxylase activity, and DNA synthesis in mouse epidermis in vivo.

When applied topically to the skin twice at a 48-h interval or thrice at 24-h intervals, 17 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) and 0.2 mumol of A23187 or ionomycin induce the same 3-fold increases of hydroperoxide (HPx) production in mouse epidermis. In contrast, these doses of Ca2+ ionophores applied once or twice at a 48-h interval produce only 3-8% of the 16- or 34-fold inductions of epidermal ornithine decarboxylase (ODC) activities caused by similar TPA treatments. However, these various Ca2+ ionophore treatments mimic entirely the stimulatory effects of TPA on epidermal DNA synthesis at 16 h and produce from 30 to 70% of the DNA responses to TPA at 32 h. Interestingly, the Ca2+ ionophore and TPA treatments applied thrice at 24-h intervals still produce above maximal or submaximal DNA responses, in spite of their very weak ODC-inducing activities or refractoriness against ODC induction. Treatment with alpha-difluoromethylornithine plus methylglyoxal bis-(guanylhydrazone) (1.25 mumol each), which inhibits the activity of the polyamine-synthesizing enzymes, does not block the HPx and DNA responses to TPA. Conversely, 1.6-25-nmol doses of fluocinolone acetonide inhibit both TPA-induced HPx production and DNA synthesis, without affecting ODC induction. The results suggest that the magnitudes of Ca2+ ionophore- and TPA-induced DNA synthesis may be linked to HPx production rather than ODC induction. Each of these three responses appears to be essential but not sufficient for tumor promotion. A23187 may be a poor or incomplete skin tumor promoter because it lacks sufficient ODC-inducing activity and cannot fully maintain the prolonged stimulation of DNA synthesis required for hyperproliferation.

Animals↗

PubMed1989

Effect of membrane potential on divalent cation transport catalyzed by the "electroneutral" ionophores A23187 and ionomycin.

Depolarization of plasma membrane potential has a potent inhibitory effect on divalent cation influx catalyzed by the carboxylic ionophores ionomycin and A23187. This effect is observed in different cell models and does not depend on either inhibition of Ca2+-activated cation channels or activation of Ca2+ extrusion mechanisms as suggested previously. A dependence of divalent cation influx on the magnitude of membrane potential is observed also in artificial liposomes. The inhibition of ionophore-dependent divalent cation transport by membrane potential depolarization can be modified varying the ionophore concentration and the external pH. These findings suggest that both neutral and positively charged ionophore-cation complexes can cross the plasma membrane and that their contribution to the overall transport process can be varied according to the experimental conditions.

Adrenal Gland Neoplasms↗

PubMed1979

The effect of ionomycin on calcium fluxes in sarcoplasmic reticulum vesicles and liposomes.

Ionomycin, a recently discovered calcium ionophore, inhibits the ATP-dependent active Ca2+ transport of rabbit sarcoplasmic reticulum vesicles at concentrations as low as 10(-8) to 10(-6) M. The effect is due to an increase in the Ca2+ permeability of the membrane which is also observed on liposomes. The inhibition of Ca2+ uptake is accompanied by an increase in the Ca2+-sensitive ATPase activity of sarcoplasmic reticulum vesicles.

Adenosine Triphosphatases↗

PubMed1993

Staurosporine-independent platelet aggregation induced by the calcium ionophore ionomycin is inhibited by prostacyclin and sodium nitroprusside and stimulated by adrenaline.

Preincubation of platelets with the protein kinase inhibitor staurosporine is known to abolish the calcium ionophore-induced ATP secretion but to decrease aggregation only partially. This indicates that, while exocytosis is necessarily connected to protein phosphorylation, a Ca(2+)-dependent aggregation occurs independently of protein phosphorylation. This aggregation pathway was inhibited by prostacyclin and sodium nitroprusside, which increase the endogenous synthesis of cyclic AMP and cyclic GMP, respectively. The effect of the cyclic nucleotides was linked to the protein phosphorylation induced by them. The staurosporine-insensitive aggregation was strongly potentiated by adrenaline, an alpha 2-adrenergic agonist; adrenaline also counteracted the inhibition induced by prostacyclin and nitroprusside, with no appreciable effect on the cAMP levels and on the cyclic nucleotide-dependent protein phosphorylation. Its effect was reversed by the alpha 2-antagonist yohimbine.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Depletion of glutathione by benzo(a)pyrene metabolites, ionomycin, thapsigargin, and phorbol myristate in human peripheral blood mononuclear cells.

Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons (PAHs) alter Ca2+ homeostasis and inhibit activation of both B and T lymphocytes obtained from rodents and humans. In the present studies, we demonstrate that alpha-naphthoflavone (ANF), an inhibitor of cytochrome P4501A activity, reduced the Ca2+ elevation produced by BaP in human peripheral blood mononuclear cell (HPBMC) lymphocytes. These results suggested that BaP metabolites may play a role in intracellular Ca2+ homeostasis in human lymphocytes. Reactive oxidative intermediates of BaP produced in HPMBC are known to be highly carcinogenic and have also been shown to be immunosuppressive. We examined the effects of benzo(a)pyrene (BaP), 7,12-dimethylbenz(a)anthracene (DMBA), benzo(e)pyrene (BeP), and anthracene, as well as certain BaP metabolites, on the levels of intracellular Ca2+ and glutathione in HPBMC. While BaP, DMBA, BeP, and anthracene did not cause a statistically significant decrease in GSH in HPBMC at concentrations of 1 or 10 microM following a 6-, 48-, or 72-hr exposure, reactive BaP metabolites including 4,5-epoxide BaP and 7,8-diol-9,10-epoxide BaP consistently produced a 20-30% depletion of glutathione in HPBMC following a 6-hr treatment period. These BaP metabolites also elevated intracellular Ca2+ in HPBMC during a 6-hr incubation. Results of these experiments suggest that metabolism of BaP to certain epoxide metabolites may be responsible for sulfhydryl damage leading to transient GSH depletion and Ca2+ elevation. These results are consistent with the hypothesis that sulfhydryl damage by certain PAH metabolites may lead to altered Ca2+ homeostasis, leading to inhibition of cell activation and proliferation in HPBMC.

Benzo(a)pyrene↗

PubMed1980

Ca2+ ionophores and the activation of human blood platelets. The effects of ionomycin, beauvericin, lysocellin, virginiamycin S, lasalocid-derivatives and McN 4308.

Platelet activation is linked to an increase in the cytoplasmic Ca2+ concentration and consequently can also be induced by ionophores which mobilize Ca2+ from intracellular storage sites or transport it through the plasma membrane. The ionophores mostly used in studies on platelet activation are A 23187 and lasalocid (X-537A). The effects of eight compounds with known Ca2+-ionophoric activity in synthetic or natural membrane systems were studied in order to investigate the relationship between transport Ca2+ and activation of platelets. Inomycin acts as a true Ca2+ ionophore: it elicits rapid shape change, aggregation, the release reaction (secretion) and clot retraction (contraction). Beauvericin activates platelets too, but probably not by increasing the cytoplasmic Ca2+ concentration. Lysocellin does not activate platelets but induces a passive loss of serotonin.

Anti-Bacterial Agents↗

PubMed1980