Differential inhibitor effects on cyclic adenosine monophosphate-phosphodiesterase isoforms in atopic and normal leukocytes.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Chan
S C
SC
Department of Dermatology, Oregon Health Sciences University, Portland 97201-3098.
Hanifin
J M
JM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012016:Reference Values
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases