Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. I. Differential Regulation of Lipopolysaccharide-Mediated Proinflammatory Cytokine (Interleukin-6 and Tumor Necrosis Factor-α) Biosynthesis in Alveolar Epithelial Cells
In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 300; no. 2; pp. 559 - 566 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.02.2002
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Subjects | |
Online Access | Get full text |
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Summary: | In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported
a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the
present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes
that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition
(8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin
(IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-α (TNF-α). Furthermore, inhibition of PDE3 (amrinone)
abolished the effect of LPS on IL-6, but attenuated TNF-α production. Reversible competitive inhibition of PDE4 (rolipram)
exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-α secretion. Blockading
PDE5 (4-{[3â²,4â²-(methylenedioxy)benzyl] amino}-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but
in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-α biosynthesis. Simultaneous inhibition
of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner,
IL-6 and TNF-α biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of
IL-6 and TNF-α. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine
biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during
the progression of inflammation within the respiratory epithelium. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.300.2.559 |