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

• Published in: The Journal of pharmacology and experimental therapeutics 2002-02, Vol.300 (2), p.559-566
• Main Authors: John J. Haddad, Stephen C. Land, William O. Tarnow-Mordi, Marek Zembala, Danuta Kowalczyk, Ryszard Lauterbach
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Interleukin-6 - biosynthesis; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Lipopolysaccharides - pharmacology; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Pulmonary Alveoli - cytology; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - metabolism; Rats; Respiratory System - metabolism; Respiratory System - pathology; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.300.2.559

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.