Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes.
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(2H)-pyridazinone-4,5- dihydro-6-[4-(1H-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.
Robicsek
S A
SA
Department of Pharmacology, College of Medicine, University of South Florida, Tampa 33612-4799.
Blanchard
D K
DK
Djeu
J Y
JY
Krzanowski
J J
JJ
Szentivanyi
A
A
Polson
J B
JB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000097:blood*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D002458:Cell Fractionation; D006152:Cyclic GMP / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000097:blood*; D008213:Lymphocyte Activation / Q000187:drug effects; D010208:Papaverine / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*
D007527:Isoenzymes; D011724:Pyridazines; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C042528:4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone; D010208:Papaverine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP