Differential inhibitor effects on cyclic adenosine monophosphate-phosphodiesterase isoforms in atopic and normal leukocytes

Sai C. Chan, Jon Hanifin

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Abstract

Increased cyclic adenosine monophosphate-phosphodiesterase activity in atopic leukocytes correlates with abnormal inflammatory and immune cell function in atopic dermatitis. The increased phosphodiesterase activity may affect many pathways of cell regulation and thus could be an important therapeutic target for management of cutaneous and respiratory inflammation. The increased PDE activities in atopic monocytes and lymphocytes reflect isoforms with increased maximum rate of metabolism but first order rate constant similar to that of the enzyme in normal cells. Both isoforms can be classed into the phosphodiesterase IV group with sensitivity to the inhibitor Ro 20-1724. In this study we used an in vitro assay to assess the effects of various phosphodiesterase inhibitors on enzyme isoforms in mononuclear leukocytes and purified leukocyte subpopulations from patients with atopic dermatitis and normal subjects. The atopic isoenzyme was found to be consistently more sensitive to a number of phosphodiesterase inhibitors. The descending order of potency for mononuclear leukocytes was rolipram, Ro 20-1724, nitraquazone, isobutyl methyl xanthine, and theophylline. Nitraquazone showed greater inhibitory effect on atopic T cells than did Ro 20-1724. Cyclic adenosine monophosphate levels increased in atopic mononuclear leukocytes incubated with Ro 20-1724 but not in normal cells. We also measured inhibitor effects on intact cells and cell homogenates, allowing discrimination of inhibitor capacity to enter intact cells. The differential inhibitor effect on various leukocyte subpopulations was demonstrated by a greater sensitivity of atopic lymphocytes and T cells for nitraquazone than for Ro 20-1724. In contrast, the latter inhibitor was a more potent inhibitor of mononuclear leukocyte and monocyte phosphodiesterase activity. This method provides a useful in vitro predictive assay of phosphodiesterase inhibitory effects on intact cell and homogenate enzymes from a variety of leukocytes involved in immune and inflammatory pathologic conditions.

Original languageEnglish (US)
Pages (from-to)44-51
Number of pages8
JournalThe Journal of Laboratory and Clinical Medicine
Volume121
Issue number1
StatePublished - 1993

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4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Phosphoric Diester Hydrolases
Cyclic AMP
Protein Isoforms
Leukocytes
Mononuclear Leukocytes
Phosphodiesterase Inhibitors
T-cells
Lymphocytes
Assays
Enzymes
Type 4 Cyclic Nucleotide Phosphodiesterase
Rolipram
Atopic Dermatitis
Xanthine
Monocytes
Theophylline
Metabolism
Isoenzymes
Rate constants

ASJC Scopus subject areas

  • Medicine(all)
  • Pathology and Forensic Medicine

Cite this

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abstract = "Increased cyclic adenosine monophosphate-phosphodiesterase activity in atopic leukocytes correlates with abnormal inflammatory and immune cell function in atopic dermatitis. The increased phosphodiesterase activity may affect many pathways of cell regulation and thus could be an important therapeutic target for management of cutaneous and respiratory inflammation. The increased PDE activities in atopic monocytes and lymphocytes reflect isoforms with increased maximum rate of metabolism but first order rate constant similar to that of the enzyme in normal cells. Both isoforms can be classed into the phosphodiesterase IV group with sensitivity to the inhibitor Ro 20-1724. In this study we used an in vitro assay to assess the effects of various phosphodiesterase inhibitors on enzyme isoforms in mononuclear leukocytes and purified leukocyte subpopulations from patients with atopic dermatitis and normal subjects. The atopic isoenzyme was found to be consistently more sensitive to a number of phosphodiesterase inhibitors. The descending order of potency for mononuclear leukocytes was rolipram, Ro 20-1724, nitraquazone, isobutyl methyl xanthine, and theophylline. Nitraquazone showed greater inhibitory effect on atopic T cells than did Ro 20-1724. Cyclic adenosine monophosphate levels increased in atopic mononuclear leukocytes incubated with Ro 20-1724 but not in normal cells. We also measured inhibitor effects on intact cells and cell homogenates, allowing discrimination of inhibitor capacity to enter intact cells. The differential inhibitor effect on various leukocyte subpopulations was demonstrated by a greater sensitivity of atopic lymphocytes and T cells for nitraquazone than for Ro 20-1724. In contrast, the latter inhibitor was a more potent inhibitor of mononuclear leukocyte and monocyte phosphodiesterase activity. This method provides a useful in vitro predictive assay of phosphodiesterase inhibitory effects on intact cell and homogenate enzymes from a variety of leukocytes involved in immune and inflammatory pathologic conditions.",
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AU - Hanifin, Jon

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N2 - Increased cyclic adenosine monophosphate-phosphodiesterase activity in atopic leukocytes correlates with abnormal inflammatory and immune cell function in atopic dermatitis. The increased phosphodiesterase activity may affect many pathways of cell regulation and thus could be an important therapeutic target for management of cutaneous and respiratory inflammation. The increased PDE activities in atopic monocytes and lymphocytes reflect isoforms with increased maximum rate of metabolism but first order rate constant similar to that of the enzyme in normal cells. Both isoforms can be classed into the phosphodiesterase IV group with sensitivity to the inhibitor Ro 20-1724. In this study we used an in vitro assay to assess the effects of various phosphodiesterase inhibitors on enzyme isoforms in mononuclear leukocytes and purified leukocyte subpopulations from patients with atopic dermatitis and normal subjects. The atopic isoenzyme was found to be consistently more sensitive to a number of phosphodiesterase inhibitors. The descending order of potency for mononuclear leukocytes was rolipram, Ro 20-1724, nitraquazone, isobutyl methyl xanthine, and theophylline. Nitraquazone showed greater inhibitory effect on atopic T cells than did Ro 20-1724. Cyclic adenosine monophosphate levels increased in atopic mononuclear leukocytes incubated with Ro 20-1724 but not in normal cells. We also measured inhibitor effects on intact cells and cell homogenates, allowing discrimination of inhibitor capacity to enter intact cells. The differential inhibitor effect on various leukocyte subpopulations was demonstrated by a greater sensitivity of atopic lymphocytes and T cells for nitraquazone than for Ro 20-1724. In contrast, the latter inhibitor was a more potent inhibitor of mononuclear leukocyte and monocyte phosphodiesterase activity. This method provides a useful in vitro predictive assay of phosphodiesterase inhibitory effects on intact cell and homogenate enzymes from a variety of leukocytes involved in immune and inflammatory pathologic conditions.

AB - Increased cyclic adenosine monophosphate-phosphodiesterase activity in atopic leukocytes correlates with abnormal inflammatory and immune cell function in atopic dermatitis. The increased phosphodiesterase activity may affect many pathways of cell regulation and thus could be an important therapeutic target for management of cutaneous and respiratory inflammation. The increased PDE activities in atopic monocytes and lymphocytes reflect isoforms with increased maximum rate of metabolism but first order rate constant similar to that of the enzyme in normal cells. Both isoforms can be classed into the phosphodiesterase IV group with sensitivity to the inhibitor Ro 20-1724. In this study we used an in vitro assay to assess the effects of various phosphodiesterase inhibitors on enzyme isoforms in mononuclear leukocytes and purified leukocyte subpopulations from patients with atopic dermatitis and normal subjects. The atopic isoenzyme was found to be consistently more sensitive to a number of phosphodiesterase inhibitors. The descending order of potency for mononuclear leukocytes was rolipram, Ro 20-1724, nitraquazone, isobutyl methyl xanthine, and theophylline. Nitraquazone showed greater inhibitory effect on atopic T cells than did Ro 20-1724. Cyclic adenosine monophosphate levels increased in atopic mononuclear leukocytes incubated with Ro 20-1724 but not in normal cells. We also measured inhibitor effects on intact cells and cell homogenates, allowing discrimination of inhibitor capacity to enter intact cells. The differential inhibitor effect on various leukocyte subpopulations was demonstrated by a greater sensitivity of atopic lymphocytes and T cells for nitraquazone than for Ro 20-1724. In contrast, the latter inhibitor was a more potent inhibitor of mononuclear leukocyte and monocyte phosphodiesterase activity. This method provides a useful in vitro predictive assay of phosphodiesterase inhibitory effects on intact cell and homogenate enzymes from a variety of leukocytes involved in immune and inflammatory pathologic conditions.

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