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

Abstract

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-␣ (TNF-␣). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-␣ production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-␣ secretion. Blockading PDE5 (4-{[3Ј,4Ј-(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-␣ biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a doseindependent manner, IL-6 and TNF-␣ biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-␣. 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.

A pathophysiological role of PDE3 in allergic airway inflammation

“…In alveolar epithelial cells, LPS-induced biosynthesis of proinflammatory cytokines is regulated by cAMP and tightly controlled by PDEs, and can be reduced by PDE inhibitors (74). Reduction in eosinophilic inflammation resulted in reduced exposure to peroxidase and peroxide and reactive oxygen species (75,76).…”

Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats

“…Since PDE5 is the predominant PDE enzyme responsible for the degradation of cGMP in the lung, PDE5 inhibitors appear to hold potential for treating pulmonary disease. In primary cultures of rat alveolar epithelial cells, blockading PDE5 with zaprinast can reduce LPS-mediated IL-6 and TNF-a biosynthesis [38]. In tracheal smooth muscle cells, zaprinast also inhibits the TNF-a-induced increase of iNOS expression and NO generation and reverses the TNF-a-induced reduction of sGCs [17].…”

Pentoxifylline Prevents Spontaneous Brain Ischemia in Stroke-Prone Rats

“…In recent years, in vitro and in vivo experiments indicated an additional therapeutic potential for PTX as an anti-inflammatory and immunomodulator agent (Teixeira et al, 1997;Laurat et al, 2001;Haddad et al, 2002). This newly described pharmacological effect can be ascribed to an inhibition of the functional responses of circulating mononuclear phagocytes, neutrophils, and T lymphocytes and the decreased synthesis of several proinflammatory cytokines (Dong et al, 1997;Neuner et al, 1997;Marcinkiewicz et al, 2000;Bahra et al, 2001;Laurat et al, 2001;Samardzic et al, 2001).…”