Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes
| Autor: | Andor Szentivanyi, James B. Polson, Joseph J. Krzanowski, Steven A. Robicsek, D. Kay Blanchard, Julie Y. Djeu |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Pharmacology
chemistry.chemical_classification 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone Cyclic nucleotide phosphodiesterase T-Lymphocytes Phosphodiesterase T lymphocyte Cell Fractionation Flow Cytometry Lymphocyte Activation Biochemistry Isozyme In vitro Isoenzymes Pyridazines Enzyme chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Cell culture Papaverine Humans Cyclic GMP Intracellular |
| Zdroj: | Biochemical Pharmacology. 42:869-877 |
| ISSN: | 0006-2952 |
| Popis: | Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that inactivate intracellular cyclic AMP (cAMP). Because the functions of T-lymphocytes are modulated by cAMP levels, the isozymes of PDE in these cells are potential targets for new drugs designed to modify the body's immunity through selective alteration of T-lymphocyte PDE activity. Cyclic GMP and 3(2 H )-pyridazinone-4, 5-dihydro-6-[4-(1 H -imidazol-1-yl)phenyl]-5-methyl-monohydrochloride (CI-930) selectively inhibit the catalytic activity of one of the two high affinity cAMP-PDE isozyme families known to occur in mammals, whereas d , l -1,4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone (Ro 20-1724) selectively inhibits the other. The objectives of this investigation were: (1) to determine whether human T-lymphocytes contain one or both of these pharmacologically distinguishable high-affinity cAMP-PDEs, and (2) to determine the effects of selective inhibitors of these PDEs on lymphocyte blastogenesis. High-affinity cAMP-PDE was found in both the soluble and particulate fractions of T-lymphocyte sonicates. Cyclic GMP and CI-930 inhibited PDE in the particulate fraction better than in the soluble fraction, but the converse was found for Ro 20-1724. CI-930 or Ro 20-1724, used alone, attenuated T-lymphocyte blastogenesis, but neither suppressed it completely. In combination, the same PDE inhibitors caused greater suppression of blastogenesis than either produced alone. The results indicate that human T-lymphocytes contain both CI-930- and Ro 20-1724-inhibitable isozymes. Either of the isozymes can modulate human T-lymphocyte blastogenesis, but inhibition of both isozymes produces synergistic antiblastogenic effects. |
| Databáze: | OpenAIRE |
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