PT  - JOURNAL ARTICLE
AU  - John J. Haddad
AU  - Stephen C. Land
AU  - William O. Tarnow-Mordi
AU  - Marek Zembala
AU  - Danuta Kowalczyk
AU  - Ryszard Lauterbach
TI  - 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
AID  - 10.1124/jpet.300.2.559
DP  - 2002 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 559--566
VI  - 300
IP  - 2
4099  - http://jpet.aspetjournals.org/content/300/2/559.short
4100  - http://jpet.aspetjournals.org/content/300/2/559.full
SO  - J Pharmacol Exp Ther2002 Feb 01; 300
AB  - 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-{[3′,4′-(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. The American Society for Pharmacology and Experimental Therapeutics