Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes

Biochem Pharmacol. 1991 Jul 25;42(4):869-77. doi: 10.1016/0006-2952(91)90047-9.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • 3',5'-Cyclic-AMP Phosphodiesterases / blood*
  • 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / pharmacology
  • Cell Fractionation
  • Cyclic GMP / pharmacology
  • Flow Cytometry
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / blood*
  • Lymphocyte Activation / drug effects
  • Papaverine / pharmacology
  • Pyridazines / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology*

Substances

  • Isoenzymes
  • Pyridazines
  • 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
  • 4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone
  • Papaverine
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic GMP